Controversies in the Psychopharmacology of Bipolar Disorder

Robert M. Post, MD (Chair)

Department of Psychiatry, George Washington University School of Medicine, Washington, DC, and the Bipolar Collaborative Network, Bethesda, Maryland

Michael J. Ostacher, MD, MPH, MMSc

Bipolar Disorder and Depression Research Program, Veterans Affairs Palo Alto Health Care System, and the Department of Psychiatry and Behavioral Sciences; Stanford University School of Medicine, Palo Alto, California

Vivek Singh, MD

Department of Psychiatry and the University Hospital Psychiatric Service, University of Texas Health Science Center at San Antonio

Controversies in the pharmacologic management of bipolar disorder were discussed in a CME symposium held in Chicago during the Current Psychiatry/American Academy of Clinical Psychiatrists 2014 Update. The goal of the symposium was to elucidate how pharmacologic and neurobiologic principles facilitate the evidence-based treatment of patients with bipolar disorder. Ongoing controversies in the pharmacologic management of bipolar disorder were addressed through interactive faculty discussion with the symposium audience. Discussion was facilitated by a series of predetermined questions divided into 3 main sections highlighting the following topics of interest:

  • Antidepressants (ADs) and bipolar disorder: perceptions and evidence
  • Mood stabilizers for the maintenance of bipolar disorder: pharmacologic principles and clinical scenarios
  • Antipsychotics in bipolar depression: evidence-based considerations

The opinions provided on these topics of interest are summarized in this review article.

Antidepressants and Bipolar Disorder: Perceptions and Evidence

Efficacy of ADs for the treatment of bipolar depression. No conventional unimodal AD is approved by the FDA for the acute or maintenance treatment of bipolar depression. However, an analysis of Surveillance Data Incorporated/Verispan’s Prescription Drug & Diagnosis Audit database, which captures data from 3,100 office-based physicians across the United States, revealed that up to 30% of bipolar treatment regimens include a conventional unimodal AD.1 The efficacy and safety of up to 16 weeks of AD treatment in adult patients in the depressive phase of bipolar I or II disorder were determined in a meta-analysis reported in the Journal of Clinical Psychiatry in 2011 (AV 1).2

AV 1. Meta-Analysis to Determine the Efficacy and Safety of Antidepressants for the Acute Treatment of Bipolar Depression (01:37)


When systematically considering all placebo-controlled studies conducted between 2003 and 2009 in which ADs were added to mood stabilizers to treat acute depression in bipolar disorder, it can be concluded from this meta-analysis that AD augmentation does not improve response or remission rates beyond the effects of mood stabilizers alone.2 Although it should be noted that ADs were not associated with an increased risk of switch into mania or hypomania, their lack of efficacy limits their clinical utility in patients with bipolar depression.2 One of the largest individual randomized, double-blind, placebo-controlled studies included in the meta-analysis was conducted by the STEP-BD collaborators (AV 2).2,3

AV 2. Efficacy and Safety of Adjunctive Antidepressant Treatment for Bipolar Depression (01:47)


As reflected by the results of the meta-analysis, no differences between ADs and placebo in percentage of patients experiencing any outcome, including transient remission, durable recovery, transient remission or durable recovery, and treatment-effectiveness response, were observed in this study.3 The patients in the mood stabilizer group showed nonsignificantly greater improvements on every outcome measure except treatment-emergent affective switch rates.3 In summary, the use of standard AD medications as adjuncts to mood stabilizers is not associated with increased efficacy or risk of treatment-emergent affective switch compared with mood stabilizers alone in people with bipolar disorder.2,3

Episode switching and course of bipolar illness in patients receiving AD therapy. Even though no difference in switch rates was observed between those patients receiving ADs and those taking placebo in the meta-analysis,2 studies have shown that some patient characteristics appear to correlate with an increased risk of switch into hypomania or mania during AD therapy.4-9 Depressed patients with bipolar II disorder who are treated with an AD adjunctive to a mood stabilizer may be less vulnerable than those with bipolar I disorder to a switch into hypomania/mania, as observed in a 10-week trial of 184 outpatients with bipolar depression (134 with bipolar I disorder, 48 with bipolar II disorder, and 2 with bipolar disorder not otherwise specified).4 Younger patient age appears to be an effect modifier on the risk of AD-associated manic conversion (ie, a new diagnosis of bipolar illness).5 Retrospective analysis of linked outpatient and pharmacy claims data for 87,920 privately insured US patients aged 5 to 29 years with an anxiety or nonbipolar mood disorder revealed that the highest rates of manic conversion associated with AD treatment occurred among children aged 10 to 14 years.5 A history of rapid cycling (>4 episodes in the past year),6,7 substance abuse and/or dependence,8 or the presence of mixed depression9 (a syndromal episode of major depression concomitant with symptoms of mania/hypomania such as motor activation, pressured speech, and racing thoughts) may also be associated with increased risk of switch into hypomania or mania in patients with bipolar disorder receiving ADs.

A systematic review and meta-analysis of randomized, controlled short-term trials of ADs for the treatment of bipolar depression published between 1980 and 2003 indicated that the rate of switching for tricyclic ADs was higher (10%) than for all other ADs combined (3.2%).10 In addition, studies have suggested that ADs with dual mechanisms of action on serotonin and norepinephrine reuptake (ie, venlafaxine) have a greater risk for inducing switching than dopamine-active agents such as bupropion and selective serotonin reuptake inhibitors (ie, paroxetine and sertraline).6,11

ADs not only lack efficacy in the acute treatment of bipolar depression, but may also worsen the long-term course of the illness, as suggested from the findings of naturalistic studies.12,13 Previous AD treatment independently predicted polarity changes (P< .001) and mixed symptoms (P  = .01) in 53 outpatients with bipolar disorder followed for more than 12 months.12 On the other hand, the number of years of mood stabilizer treatment was an independent predictor of more time spent being asymptomatic (P = .019). Greater AD exposure compared with mood stabilizer exposure was associated with less time being asymptomatic (P = .03), more mixed symptomatology (P = .019), and more polarity changes (P = .001).12 In 139 outpatients with bipolar I disorder followed for at least 6 months, treatment nonresponse to ADs was independently linked to a greater number of prior AD trials, as well as a history of a comorbid anxiety disorder and more prior depressive episodes.13

Although some data do suggest efficacy of ADs in bipolar II disorder, the risks of cycle acceleration and greater numbers of depressive recurrences, especially in rapid cyclers, have been noted.7

AD continuation versus discontinuation in patients with bipolar disorder.
AD continuation may be effective in the small number of patients with bipolar disorder who initially respond to acute treatment with ADs and maintain this response for several months without an affective switch, although this appears to occur in only a minority (about 15%) of patients.7,14-16 In a prospective 1-year follow-up observational study from 2003, only 36% of 41 patients who remained on ADs following at least 6 weeks of initial effective treatment had relapsed into a new depression by week 48, compared with 70% of 43 patients who had stopped ADs following the initial 6 weeks of effective treatment.15 Although no statistically significant symptomatic benefit of AD treatment was observed in a STEP-BD randomized clinical trial, trends toward mild benefits were noted in patients who continued ADs after recovery from acute bipolar depression.16 It was noted, however, that AD continuation increased the number of depressive recurrences among rapid cyclers.16 The modest benefits of AD continuation observed in these studies may be applicable to only a minority of the bipolar population,14-16 and the characteristics of patients with bipolar disorder who may benefit from AD treatment have yet to be determined.7

AD use in patients with bipolar disorder: a summary. Relatively few data support the efficacy of ADs in patients with acute bipolar depression.2 ADs with dual mechanisms of action on serotonin and norepinephrine reuptake may increase switch rates,6,11 and AD use may be associated with poor long-term outcomes such as mood switches and cycle acceleration, although it is not yet clear whether this is a causal relationship.13 Unfortunately, AD use in patients with bipolar disorder is still prevalent, and one possible reason for this is that “physicians…were not prepared to discard therapies validated by both tradition and their own experience on account of somebody else’s numbers,”17,18 especially when there were no other alternatives. However, as discussed below, evidenced-based options are now available that are FDA approved.

The controversy surrounding AD use was recently noted in the ISBD task force report on AD use in bipolar disorders, which stated that “there is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder.”19 Although the ISBD task force cited insufficient evidence for global treatment benefits of ADs combined with mood stabilizers, they did acknowledge that individual patients with bipolar disorder may benefit from ADs.19 However, they also noted that patients with bipolar I disorder should be prescribed ADs only as an adjunct to mood stabilizers.19 Efficacious alternatives to ADs were discussed at this symposium and are addressed in the next sections of this article.


Mood Stabilizers for the Maintenance of Bipolar Disorder: Pharmacologic Principles and Clinical Scenarios

Rationale for effective maintenance therapies. One of the main goals of maintenance treatment in bipolar disorder is to prevent the recurrence of affective episodes. Patients who do not achieve remission and continue to experience low levels of symptoms have higher relapse and recurrence rates. Persistent symptoms impair psychosocial functioning and increase the probability that the illness will become treatment refractory.20 A pooled data analysis of depression studies showed that patients with 1 to 5 previous episodes were 40% more likely to respond to treatment compared with those patients with >10 episodes (odds ratio = 1.6; 95% CI 1.02–2.40).20 These data indicate that treatment refractoriness is directly related to the frequency of affective episodes.

Mood episodes may cause changes in the brain that might be associated with subsequent treatment refractiveness.21 Manic and depressive episodes decrease levels of brain-derived neurotrophic factor, increase oxidative stress, and are associated with decreased prefrontal cortex volume and increased amygdala function.21 An increased number of depressive episodes was associated with greater cognitive dysfunction, more disability, medical comorbidities, late-life dementia, and an increased load of short telomeres.21-23 Because mood episodes appear to alter brain processes, cause significant dysfunction, and lead to treatment refractoriness, prevention of relapse and recurrence of mood episodes should be the primary long-term goal of bipolar disorder therapy.

Choosing therapies for the maintenance of bipolar disorder: clinical evidence. The goal of the BALANCE study, published in 2010 in Lancet, was to determine whether the initial use of combination therapy (ie, lithium plus valproate) was more effective than monotherapy (ie, lithium or valproate) for the maintenance treatment of bipolar disorder (AV 3).24

AV 3.Relapse Prevention in Bipolar I Disorder (BALANCE): A Randomized Open-Label Trial (01:45)


BALANCE was a randomized, open-label, maintenance therapy trial in patients with bipolar I disorder, which included up to 24 months of follow-up. All patients initially received 4 to 8 weeks of combination therapy (lithium plus valproate) to identify those patients who would be able to tolerate both drugs upon randomization.24 The primary outcome of initiation of a new intervention for an emergent mood episode occurred during the follow-up period in 59 of 110 (54%) of participants who received combination therapy, 76 of 110 (69%) who received valproate, and 65 of 110 (59%) who received lithium carbonate.24 Hazard ratios for the primary outcome were 0.59 (95% CI 0.42–0.83; P = .0023) for combination therapy versus valproate, 0.82 (0.58–1.17; P = .27) for combination therapy versus lithium, and 0.71 (0.51–1.00; P = .0472) for lithium versus valproate.24 The results of the BALANCE study suggest that monotherapy with valproate should be avoided as a first-line treatment. Whether combination therapy is preferable to lithium monotherapy in patients with bipolar disorder was unclear.24 It may be advisable to initiate patients on lithium monotherapy and add in valproate if no improvement in symptoms is observed with lithium alone.24

Possible clinical predictors of responsiveness to the mood stabilizers lithium, carbamazepine, valproate, and lamotrigine are detailed in Table 1.7,21,25,26 These predictors are derived from secondary analyses of clinical trials, so they should be interpreted with caution. Clinical predictors of lithium responsiveness include classic bipolar illness with discrete episodes and euthymic intervals, euphoric rather than dysphoric mania, no anxiety comorbidity, no substance abuse comorbidity, and no psychosis.21 Lithium responders also tend to have a positive family history of mood disorder and especially a positive family history of lithium responsiveness.21 Clinical predictors of carbamazepine responsiveness appear to be generally opposite of those for lithium responsiveness and include a negative family history of bipolar illness.21

Choosing therapies for the maintenance of bipolar disorder: clinical judgment. Practitioners should exercise clinical judgment to augment the available evidence regarding the types of mood stabilizers and other therapies that should be used in patients with bipolar illness. Clinical judgment may be facilitated by remembering the concept of “STEPSS to a rational choice”27:

  • SAFETY (acute therapeutic index, long-term safety, drug‒drug interactions)
  • TOLERABILITY (acute and long term)
  • EFFICACY (overall efficacy, unique efficacy, onset of action, maintenance efficacy)
  • SIMPLICITY OF ADMINISTRATION (ease of optimal dosing, need to adjust dosing, frequency of dosing, need for specific monitoring)
  • SIDE EFFECTS (in a positive context)

Treatment selection should be personalized to the patient; personalized medicine does not mean that clinicians should be prescribing medications based on their own personal preferences in the absence of supporting data. Clinicians should have a complete understanding of their patients (eg, comorbid conditions, other medical conditions) and then should initially consider using evidence-based therapies, followed by less well-validated options as a patient’s lack of response might dictate. Treatment response should be monitored by encouraging patients to fill in mood questionnaires and/or by administering rating scales on a regular basis, which enables patients to provide feedback regarding how they are feeling and whether they are experiencing side effects.7

Clinical decision making upon observation of a partial response. If a partial response to a mood stabilizer is observed, clinicians should consider using other pharmacologic or psychotherapeutic options to increase the chances of obtaining complete remission. Options for the treatment of bipolar depression include the following:

  • Second-generation antipsychotics: quetiapine, lurasidone, olanzapine-fluoxetine combination28-31
  • Combination of a mood stabilizer and a second-generation antipsychotic: lurasidone added to lithium or valproate32
  • Lithium28,33
  • Anticonvulsants: lamotrigine28,34
  • Psychotherapy28
  • Electroconvulsive therapy, repetitive transcranial magnetic stimulation35,36
  • Adjunctive medications: pramipexole, triiodothyronine, modafinil, folate, vitamin B, N-acetylcysteine, ADs28,35,37-39

The adjunctive medications listed above have not been confirmed as clinically effective in adequately powered clinical trials, so the use of these medications cannot be viewed as being evidence based. As discussed earlier, there is no conclusive evidence to support the routine use of ADs in bipolar disorder. N-acetylcysteine can be obtained over the counter, and while not FDA approved for the treatment of bipolar disorder, it may be efficacious for the treatment of a variety of pathologic habits (eg, addictions to substances such as cocaine, heroin, alcohol, and marijuana; gambling; and trichotillomania) and may also be used for the treatment of mood disorders including bipolar depression. Benefit may be observed as early as 8 weeks.40-42 Although N-acetylcysteine was shown in a double-blind, randomized, placebo-controlled trial in 75 individuals to be a safe and effective augmentation strategy for treating depressive symptoms in bipolar disorder,42 no significant differences versus placebo were observed after 149 patients who improved on N-acetylcysteine over 8 weeks were randomized to placebo or continuation therapy.43

Patients with bipolar disorder are typically receiving more than 1 medication and have a number of comorbid psychiatric and/or medical conditions. Substance use disorders are highly prevalent in bipolar disorder yet the effectiveness of therapies in patients with bipolar disorder who abuse substances such as alcohol, cocaine, or nicotine has not been well studied.7,21 Topiramate may be effective for the treatment of bulimia and alcohol or cocaine dependence, yet it does not have antimanic properties. Bupropion (used with close follow-up and monitoring), nicotine replacement, and varenicline may be options for those patients who want to quit smoking.7,21

Using combination therapy in bipolar disorder. The use of combination therapy allows treatment of the full spectrum of bipolar symptomatology, including symptoms of anxiety, symptoms of psychosis, psychotic symptomatology, mood symptomatology, behavioral disturbances, and possibly cognitive difficulties. Combination therapy may allow the use of lower and better tolerated doses of medications and therefore could even have a safety advantage over high-dose monotherapy, although to date no studies comparing combination therapy with monotherapy have suggested such an advantage; in fact, combination therapy is nearly always associated with more adverse effects.7 The concept of combination therapy resulting in fewer side effects is controversial, but if patients receiving combination therapy are managed appropriately, they may have a greater chance of achieving symptom improvement or remission than those who receive monotherapy with escalating doses that may eventually rise above the side-effect threshold.7 In any case, it is always recommended to use adequate doses of any treatment because lower doses can be expected to be less effective.

Most second-generation antipsychotics are FDA approved as adjuncts to mood stabilizers.44-47 Aripiprazole, risperidone LAI, quetiapine, and ziprasidone are FDA approved as adjuncts to lithium or valproate for the maintenance treatment of bipolar I disorder.44-47 Aripiprazole and risperidone LAI are also indicated as monotherapies for the maintenance treatment of bipolar I disorder, along with olanzapine.44,45,48 Olanzapine, asenapine, and oral risperidone are indicated as adjunctive therapies to lithium or valproate only for the acute treatment of manic or mixed episodes.45,48,49 A number of studies have suggested that combination therapies are more effective than monotherapy for the maintenance treatment of bipolar disorder; these include studies of lithium and valproate,24 lithium and carbamazepine,50 and valproate plus lamotrigine.51 For example, valproate plus lamotrigine is more effective than lamotrigine alone at preventing episodes, especially of depression.51

Patients receiving combination therapies should be continually assessed for tolerability issues, and treatment nonadherence should be addressed by initiating open and straightforward conversations with patients.7

Antipsychotics in Bipolar Depression: Evidence-Based Considerations

The need for more FDA-approved therapies. There is a significant unmet need for more FDA-approved therapies for both acute depressive episodes and symptom maintenance in patients with bipolar disorder. Only the following therapies are FDA approved for the treatment of acute bipolar depression: olanzapine-fluoxetine,29 quetiapine,30 quetiapine XR,52 and lurasidone.31,32 Lurasidone is the only agent approved both as a monotherapy and as an adjunctive therapy to a mood stabilizer (lithium or valproate).31,32 Because the FDA-approved therapies for acute bipolar depression are limited to 4 second-generation antipsychotics, it is important to understand and monitor for associated receptor-medicated side effects, which may need to be addressed to facilitate treatment adherence. The differing side-effect profiles of second-generation antipsychotics may be dependent upon their activities at a variety of receptors, including the histamine-1 receptor (negative effects of receptor blockade include sedation, drowsiness, weight gain), the dopamine D2 receptor (negative effects of receptor blockade include hyperprolactinemia, extrapyramidal symptoms, tardive dyskinesia), and the α-1 receptor (negative effects include reflex tachycardia, hypotension, dizziness).21

Rationale for screening patients with bipolar disorder for metabolic conditions. Mental health clinicians are aware of the potential for antipsychotics to cause metabolic dysfunction, which is especially relevant because patients with bipolar illness are highly susceptible to obesity, cardiovascular disease, diabetes, and the metabolic syndrome. The metabolic effects of second-generation antipsychotics must be considered when making treatment choices for patients with bipolar disorder.53,54

AV 4. Relationship Between Obesity and Likelihood of Recurrence of Bipolar Depression (01:04)


Medical comorbidities are common in patients with bipolar disorder. Statistical evaluations based on a MEDLINE search of all English-language articles published between January 2004 and November 2006 revealed the following mean rates of comorbid conditions in patients with bipolar disorder: overweight (49%), obesity (30%), metabolic syndrome (30%), dyslipidemia (29%), hypertension (26%), cardiovascular disease (23%), type 2 diabetes (10%), and stroke (2%).55 Unfortunately, medical comorbidities such as obesity may influence the course of bipolar illness.56 The relationship between obesity and the likelihood of a recurrence of bipolar depression was examined in 175 patients treated for an acute affective episode and followed through maintenance therapy.56 Time to recurrence of depression was shorter in the obese patients than in the nonobese patients (AV 4).56

Preventing and treating obesity in patients with bipolar disorder could improve the course of this chronic illness. Clinicians should routinely assess for other medical conditions in their patients and be sensitive to the presence of comorbid medical conditions when choosing medications to treat bipolar disorder.

Choosing an FDA-approved antipsychotic to treat bipolar depression. The number needed to treat (NNT) and number needed to harm (NNH), calculated based on data from randomized, controlled registration trials, can help clinicians choose the optimal FDA-approved second-generation antipsychotic to treat bipolar depression (Table 2).57

NNT is the number of people who need to receive a medication in order for 1 patient to have the desired effect. Generally, an NNT value of less than 10 is considered effective. Olanzapine-fluoxetine combination, quetiapine, and lurasidone all have single-digit NNT values for both response and remission (see Table 2).57 NNH is the number of people who need to receive a medication in order for 1 patient to experience harm from the medication, when compared with those receiving placebo—in this case, the larger the NNH, the lower the probability that a patient will experience adverse effects. The single-digit NNH values for olanzapine-fluoxetine regarding weight gain and diarrhea, and for quetiapine regarding somnolence and dry month, can be interpreted as meaning that these side effects are commonly observed in patients receiving these antipsychotics (see Table 2).57

When choosing a medication to treat bipolar disorder, it is important to balance the evidence related to both efficacy and side effects/tolerability. Clinicians should consider therapeutic effectiveness, and not just efficacy, when making treatment decisions. Although the evidence may suggest that a medication is 100% efficacious, its effectiveness will be 0% if the medication is not tolerated or not taken by the patient. Thus, effectiveness is a function of both efficacy and treatment adherence.7 Adverse effects are the most common reason why people with bipolar disorder discontinue medication both in the short term and long term.7


Bipolar disorder is highly complex and often treatment resistant. Evidence-based approaches to acute and maintenance therapy should be implemented early and used persistently to maximize the probability of symptom control and relapse prevention. To that effect, ADs for bipolar depression should generally be avoided. Treatment resistance, cognitive dysfunction, and medical comorbidities all increase with the number of affective episodes,20,58 so that long-term treatment of bipolar disorder typically requires multimodal, complex combination therapy. It is critical to continuously educate patients about preventing episodes and protecting themselves from the many potential issues associated with bipolar disorder. Both patients and clinicians need a new mantra: “Prevent episodes to protect the body and the brain.”

Clinical Points

  • Be aware of the lack of evidence regarding the efficacy of conventional unimodal ADs for the treatment of bipolar depression
  • Appreciate that AD continuation following an acute response to the AD may be effective in only a minority of patients with bipolar disorder
  • Develop individualized, evidence-based strategies to ensure the effective use of therapies such as mood stabilizers and antipsychotics in patients with bipolar disorder
  • Recognize that lithium monotherapy may be as effective as combination therapy (lithium plus valproate) when considering initial treatment strategies for the maintenance of bipolar disorder
  • Consider evidence-based benefit/harm calculations when choosing a treatment for bipolar depression

Drug Names

aripiprazole (Abilify), asenapine (Saphris), bupropion (Aplenzin, Wellbutrin, and others), carbamazepine (Equetro, Tegretol, and others), lamotrigine (Lamictal and others), lithium (Lithobid and others), lurasidone (Latuda), modafinil (Provigil and others), olanzapine (Zyprexa and others), olanzapine-fluoxetine combination (Symbyax and others), paroxetine (Paxil, Pexeva, and others), pramipexole (Mirapex and others), quetiapine (Seroquel and others), quetiapine XR (Seroquel XR), risperidone (Risperdal and others), risperidone LAI (Risperdal CONSTA), sertraline (Zoloft and others), topiramate (Topamax and others), varenicline (Chantix), venlafaxine (Effexor and others), ziprasidone (Geodon and others)


AD = antidepressant; BALANCE = Bipolar Affective disorder: Lithium/ANti-Convulsant Evaluation; CI = confidence interval; FDA = US Food and Drug Administration; ISBD = International Society for Bipolar Disorders; LAI = long-acting injection; Li = lithium; MEDLINE = Medical Literature Analysis and Retrieval System Online; NNH = number needed to harm; NNT = number needed to treat; SA = schizoaffective illness; STEP-BD = Systematic Treatment Enhancement Program for Bipolar Disorder; STEPSS = Safety, Tolerability, Efficacy, Price, Simplicity of administration, Side effects; XR = extended release


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