47,49 These studies did not detect any benefit from lamotrigine on the primary

end points (change in Hamilton Depression Rating Scale [HAM-D], or Montgomery–

Åsberg Depression Rating Scale [MADRS]) relative to placebo. An independent

meta-analysis of the same five studies found significant (but only modest) benefits for

lamotrigine with a relative risk of response of 1.27 for the HAM-D and 1.22 for the

MADRS.

166 The ability of lamotrigine to reduce the risk of relapse to depression is

less controversial. A pooled analysis of two long-term studies (up to 18 months) with

lamotrigine found a 36% reduction in the risk of relapse to depression.

167

Lamotrigine was well tolerated with no difference from placebo in any side effect.

Because lamotrigine has limited antimanic properties, patients with a history of

severe, recent, or recurrent mania should only take lamotrigine in combination with

an antimanic drug, such as lithium.

46

The combination of lamotrigine and lithium may confer additional benefits on

reducing depressive symptoms and should be considered for bipolar depression.

Patients stabilized on lithium (predefined range of 0.6–1.2 mEq/L, mostly >3 months’

duration) were randomly assigned to receive lamotrigine (200 mg/day) or placebo.

The lithium–lamotrigine group had a response rate of 52% (based on MADRS

scores) compared with 32% for the lithium–placebo group.

168 From the results of this

study, clinical experience, and the need for long-term tolerability, the combination of

lamotrigine and lithium is an appropriate treatment when monotherapy with these

drugs has failed.

Due to valproate’s inhibition of UGT2B7, it can increase lamotrigine’s AUC by

2.6-fold. Clinicians should pay particular attention to the dosing with initiating or

discontinuing either medication in the presence of the other medication.

91

Atypical Antipsychotics

AAPs offer another option for the treatment of bipolar depression. Quetiapine has

demonstrated efficacy in a total of four 8-week double-blind, placebo-controlled

studies (300 or 600 mg/day).

169–172 Response rates ranged from 58% to 69% for the

300-mg dose, and 58% to 70% for the 600-mg dose. Both doses were commonly

associated with sedation, somnolence, dry mouth, and dizziness. Clinically

significant weight gain (≥7% of baseline weight) was detected in roughly 5% to 10%

of subjects receiving quetiapine.

The combination of olanzapine with fluoxetine is effective for patients with

bipolar depression.

173

In a 7-week acute-phase treatment, OFC was superior to

lamotrigine in symptom improvement but not significantly different in response rate

(69% with OFC vs. 60% with lamotrigine).

174 The rate of relapse to depression

during the 6-month study was low and similar between OFC and lamotrigine (14%

vs. 18%). In an extension of this study (for a total of 6 months), OFC caused

significant elevations in all metabolic parameters (weight, glucose, prolactin,

cholesterol).

175 Most alarming was a 34% incidence of clinically significant weight

gain in the OFC group (vs. 2% with lamotrigine). Therefore, the risk of metabolic

complications should be taken into consideration when selecting this treatment.

Lurasidone has demonstrated efficacy in two 6-week, randomized, double-blind

controlled clinical trials as monotherapy at either 20 to 60 mg/day and 80 to 120

mg/day. Response rates were 53% for the low dose, 51% for the high dose, and 30%

for placebo. An additional study with a similar design failed to separate from

placebo. An adjunct to lithium or VPA trial demonstrated response rates of 57% of

lurasidone with either lithium or VPA compared to 42% of placebo with either

lithium or VPA.

176–178 Table 87-7 provides dosing information for AAPs approved

for the treatment of bipolar depression.

Despite its efficacy in treatment-resistant unipolar depression, aripiprazole does

not appear to be effective for bipolar depression on the basis of two randomized,

controlled trials.

172 , 179 Considering these findings, the CANMAT guidelines have

listed aripiprazole as not recommended for acute bipolar depression.

49 Other AAPs

have not been systematically studied in bipolar depression.

Antidepressants

The use of antidepressants in BD has been hotly debated. Some guidelines

recommend restrictive use of antidepressants because of concerns about mood

switching and cycle acceleration.

48 Other guidelines recommend early treatment with

antidepressants, particularly SSRIs, to address the recurrent depressive episodes.

47

In either case, there is agreement that antidepressants should only be used in

combination with antimanic agents such as VPA, lithium, or an AAP.

47,48 The largest

controlled trial of antidepressant augmentation in bipolar depression was conducted

as part of the Systematic Treatment Enhancement Program for Bipolar Disorder

(STEP-BD) study. This study was a naturalistic 26-week, double-blind, placebocontrolled trial comparing antidepressants (bupropion or paroxetine) with placebo as

adjunctive treatment to an antimanic agent.

81 The primary end point of durable

recovery (euthymia for 8 weeks) was achieved in 24% of antidepressant-treated

subjects compared with 27% receiving placebo. There was no significant difference

between groups in treatment emergent mood switch. A recent meta-analysis of 15

studies, primarily with bupropion or SSRIs, found that antidepressants were no more

effective than placebo for acute (<16 weeks) bipolar depression.

180 This study also

did not find an increased risk of mood switch. Therefore, although it appeared to be

safe to add the antidepressant in regard to switching into mania, there is question

about whether there is a large benefit on depressive symptoms.

Table 87-7

Atypical Antipsychotic Dosing in Bipolar Depression

Atypical Antipsychotic Initial Dose Titration Effective Dose Range

Lurasidone 20 mg/day 20 mg every 2 days 20–120 mg/day

Olanzapine/Fluoxetine 6/25 mg/day As indicated 12/50 mg/day

Quetiapine (IR and XR) 50 mg/day 100 mg Day 2

200 mg Day 3

300 mg Day 4

300 mg/day

Source: Latuda (lurasidone) [package insert]. Marlborough, MA: Sunovion Pharmaceuticals; July 2013; Symbyax

(olanzapine/fluoxetine) [package insert]. Indianapolis, IN: Lilly USA, LLC.; January 2015; Seroquel XR

(quetiapine XR) [package insert]. Wilmington, DE: AstraZeneca; July 2009.

p. 1847

p. 1848

Because H.C. did not respond to lithium in combination with VPA during her past

depressive episode, an alternative first-line agent such as lamotrigine is a reasonable

choice. OFC or quetiapine may compromise her type 2 diabetes control and thus are

not appropriate options. Lurasidone would also be an alternate choice, although no

current data exist in comparing it to lamotrigine, quetiapine, or OFC for the treatment

in bipolar depression. Dosing of lamotrigine needs to account for H.C.’s concurrent

use of VPA, which is known to inhibit the metabolism of lamotrigine. Therefore, the

initial dose for H.C. is 25 mg every other day for weeks 1 and 2 followed by an

increase to 25 mg/day for weeks 3 and 4. The dose can be increased to 50 mg/day for

week 5 and then to a maximum of 100 mg/day beginning at week 6. In the absence of

VPA, the recommended target dose of lamotrigine is 200 mg/day. In patients taking

enzyme inducers (e.g., CBZ), the target dose is 200 mg twice daily.

181 The

appropriate titration schedule must be followed for lamotrigine (see also Chapter 60,

Seizure Disorders) because of the risk of skin rash, which may progress to the lifethreatening Stevens–Johnson syndrome. The combination of lamotrigine and VPA is a

risk factor for the development of this dangerous cutaneous reaction; therefore, H.C.

should be instructed to contact her physician immediately if a skin rash develops.

MAINTENANCE THERAPY OF BIPOLAR

DISORDER

CASE 87-8

QUESTION 1: R.L., a 33-year-old man, has been treated for an episode of acute mania with lithium 600 mg

twice a day for 3 weeks. He is no longer overtly manic. Because of R.L.’s past episodes of depression and

mania, his physician decides to institute prophylactic (maintenance) lithium therapy. What are the goals of

maintenance lithium therapy for R.L.? How should he be monitored during this maintenance phase? How long

should R.L. be maintained on lithium?

Recurrent episodes are associated with decreased quality of life, poorer response

to treatment, longer hospitalizations, and cognitive impairment.

35 Thus, early

maintenance (prophylactic) treatment is indicated to prevent disease progression.

Appropriate goals for maintenance therapy include an increase in the interval

between episodes, a decrease in the frequency of episodes, and a reduction in the

duration and severity of mood episodes. In most cases, patients will have been

started on an acute treatment for a manic or depressive episode. These agents should

generally be continued because abrupt switches in medications may predict poorer

treatment outcomes.

35

Lithium

The aforementioned meta-analysis (Case 87-7, Question 1) of long-term lithium

therapy for relapse prevention in BD included five randomized, placebo-controlled

studies.

163 Although lithium did not effectively reduce the risk of relapse to

depression, it did reduce the risk of relapse to any mood episode (risk ratio, 0.66)

and to manic episodes specifically (risk ratio, 0.62). The average risk of relapse to

any mood episode on lithium was 40% versus 60% for placebo. The average risk of

relapse to a manic episode was 14% for lithium versus 24% for placebo.

In the case of R.L., he should be continued on lithium. The target levels for

maintenance therapy with lithium should be in the range of 0.5 to 0.8 mEq/L.

11 Higher

levels ranging from 0.8 to 1.0 mEq/L are associated with a reduced number of

relapses (compared with levels between 0.4 and 0.6 mEq/L) but also have an

elevated risk of side effects.

182

In addition to determining an appropriate maintenance lithium level for R.L., it is

important to consider whether once-daily administration of lithium can improve

adherence or adverse effects. During periods of dosage readjustment, R.L. will

require monitoring of his lithium serum level more frequently. Once stabilized, the

monitoring frequency can be reduced to quarterly. See Table 87-3 for recommended

lithium monitoring guidelines.

CASE 87-8, QUESTION 2: What other maintenance treatments for BD are available should R.L. fail to

respond to lithium?

Anticonvulsants

VPA and lamotrigine are reasonable alternatives to lithium that have shown efficacy

in BD maintenance therapy. In the first controlled trial of VPA for the maintenance

treatment of BD, patients were randomly assigned to receive VPA, lithium, or

placebo and followed for 52 weeks.

183 The three groups did not differ with regard to

the primary outcome of time to any mood episode. However, a lower percentage of

patients discontinued treatment for any reason in the VPA group (62%) than lithium

(76%) or placebo (75%); patients on VPA remained in the study longer (198 days)

than patients on lithium (152 days) but not placebo (165 days). The mean VPA serum

concentration was 85 mcg/mL. Lamotrigine has been studied rigorously in the

maintenance treatment of BD. A pooled analysis of two placebo-controlled studies

found that lamotrigine and lithium more than doubled the time to intervention (e.g.,

addition of pharmacotherapy or ECT) for any mood episode compared with placebo

(s e e Case 87-7, Question 1).

167 The time to intervention was 197 days for

lamotrigine, 187 days for lithium, and 86 days for placebo. Lithium preferentially

prevented manic relapses, whereas lamotrigine preferentially prevented depressive

episodes.

Atypical Antipsychotics

AAPs have become increasingly popular alternatives and adjunctive treatments for

maintenance therapy of BD. To date, aripiprazole, olanzapine, quetiapine

(adjunctive), risperidone long-acting injection, and ziprasidone (adjunctive) have

received FDA approval for the maintenance treatment of BD (Table 87-8). A metaanalysis evaluated 20 trials (n = 5364) in the efficacy of maintenance treatments for

BD. No monotherapy options were associated with significantly reduced risk for

both manic/mixed and depressive poles compared to each other, while the only

combination, quetiapine plus lithium or VPA demonstrated significant reduction in

risk versus the comparator of placebo in reduced risk for both poles.

184 The long-

term risk of side effects, including metabolic complications and EPS, should be the

primary consideration for selecting one AAP over another (see Case 87-5, Question

1).

CASE 87-8, QUESTION 3: What is the role of psychotherapy in BD?

Psychotherapy can have a profound effect on the prevention of acute illness, as

well as a sustained effect on maintenance treatments. Excessive stress, for example,

is often implicated in the onset of affective episodes, particularly early in the lifetime

course of BD.

7

If individuals and their families can learn to avoid these triggers or to

develop coping skills, the acute impact can be minimized and future episodes

averted.

Therapy may also help the family to cope with the extreme emotions and disruption

that are the hallmark of acute manic and depressive episodes. Violent outbursts,

infidelity, financial debts, substance abuse, suicidal thinking, and loss of self-esteem

may all be a byproduct of mood recurrence, and family members must come to terms

with such calamities, as well as fears surrounding future episodes. Regular sleep–

wake cycles seem vital to the maintenance of euthymic states; thus, improvements in

sleep hygiene may be encouraged in these sessions. Last, sustained medication

adherence must also be emphasized; individuals with BD will often stop their

medications in an effort to resume the “highs” of mania or because of the cumulative

side effect burden of complex psychotropic regimens.

p. 1848

p. 1849

Table 87-8

FDA-Approved Medications for Bipolar Disorder

Drug Mania Mixed Depression Maintenance

Carbamazepine (extended-release capsule) X X

Lamotrigine X

Lithium X X

Valproate (divalproex sodium) X X

Asenapine X X

Aripiprazole X X X

Lurasidone X

a

Olanzapine X X X

Olanzapine–fluoxetine X

Quetiapine X X X

a

Quetiapine XR X X X X

a

Risperidone long-acting injection X

Risperidone X X

Ziprasidone X X X

a

aMonotherapy or adjunct to lithium or valproate.

FDA, Food and Drug Administration.

The specific psychotherapeutic approach to BD is generally quite similar to

interventions offered to individuals with schizophrenia. Family-focused therapy

seems to be quite effective, as are cognitive-behavioral and interpersonal and social

rhythm therapy. Collaborative care models have been extensively studied for

unipolar depression in primary-care settings, but the effectiveness of collaborative

care models for bipolar illness is less clear. In fact, in the STEP-BD trials,

collaborative care was the least effective intervention.

185 Reported response rates

were 77% with family-focused therapy, 64% with interpersonal and social rhythm

therapy, 60% with cognitive-behavioral therapy, and 54% with collaborative care.

Experts contend that the collaborative care intervention was comparatively less

intensive than the other three treatment modalities in this report.

Although most experts advocate for regular physical activity to prevent bipolar

mood swings, the body of literature supporting such an approach is very limited.

Lifestyle surveys have demonstrated that people afflicted with BD are less likely to

exercise and more likely to exhibit poor dietary habits than those without a serious

mental illness.

186 Theoretically, exercise may improve dietary habits, regulate sleep,

increase energy, and promote euthymic moods. As a result, increased physical

activity would be expected to improve the prognosis of bipolar illness and should be

encouraged at the very least for the physical health benefits.

CASE 87-8, QUESTION 4: Are there other treatment options for BD?

Alternative Medicines

A wide variety of herbal preparations and dietary supplements have been studied for

the treatment of BD. A meta-analysis of double-blind, placebo-controlled trials of

combined bipolar and unipolar depression found significant benefit of omega-3 fatty

acid supplementation compared with placebo in patients with depressive episodes.

187

In most cases, omega-3 fatty acid supplementation, including eicosapentaenoic acid

alone or in combination with docosahexaenoic acid, was used as adjunctive

treatment. The doses studied ranged from 1 g/day of eicosapentaenoic acid to 9.6

g/day of combined eicosapentaenoic acid and docosahexaenoic acid.

Inositol was recently compared with lamotrigine and risperidone in an

augmentation trial for bipolar depression.

188 The three treatments were equivalent

with regard to recovery from depression; however, the study was open label and the

sample size was small (n = 66). Saint-John’s-wort and S-adenosyl-L-methionine may

be effective for depressive episodes; however, these agents, like traditional

antidepressants, should generally be avoided in BD owing to the risk of mood

destabilization.

55,56

Electroconvulsive Therapy

ECT is effective in all phases of BD and continues to play a vital role in the

contemporary treatment of mood disorders. The efficacy of ECT in bipolar

depression is equivalent to unipolar depression with approximately 80% of patients

achieving a response and 60% meeting criteria for remission.

189 The benefits of ECT

in acute mania are similarly impressive. In a review spanning 50 years of research,

“remission or marked clinical improvement” was achieved in 80% of patients.

190,191

BD medication regimens need to be carefully evaluated before ECT treatment.

Anticonvulsants and benzodiazepines raise the seizure threshold and interfere with

the effectiveness of ECT. A retrospective analysis found that patients taking

anticonvulsants achieved the same overall clinical response but required more ECT

treatments and a longer hospital stay.

192 An exception is the concurrent use of

lamotrigine, which appears to have no significant effect on electrical stimulus dose

or seizure duration.

193 Lithium use with ECT has been discouraged on the basis of

early reports of organic brain syndrome; however, a more recent prospective study

found the combination to be safe in a younger population

p. 1849

p. 1850

without risk factors for ECT complications.

194,195 Small case series and clinical

experience suggest that AAPs are safe to use during ECT.

196–198

ECT remains an effective and important tool for the treatment of BD, particularly

bipolar depression, which is highly recurrent and has limited safe and effective

treatment options. All patients failing to respond to standard BD pharmacotherapy,

presenting with severe mood symptoms, or not otherwise appropriate for medication

treatment should be considered for ECT.

KEY REFERENCES AND WEBSITES

A full list of references for this chapter can be found at

http://thepoint.lww.com/AT11e. Below are the key references and websites for this

chapter, with the corresponding reference number in this chapter found in parentheses

after the reference.

Key References

American Diabetes Association et al. Consensus development conference on antipsychotic drugs and obesity and

diabetes. Diabetes Care. 2004;27:596. (125)

American Psychiatric Association. Mood disorders. In: American Psychiatric Association, ed. Diagnostic and

Statistical Manual of Mental Disorders. 5th ed. Text Revision. Washington, DC: American Psychiatric

Association; 2013:123. (5)

Cipriani A et al. Comparative efficacy and acceptability of antimanic drugs in acute mania: a multiple-treatments

meta-analysis. Lancet. 2011;378:1306–1315. (123)

Cipriani A et al. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood

disorders: a systematic review of randomized trials. Am J Psychiatry. 2005;162:1805. (164)

Crismon ML et al. Texas Medication Algorithm Project Procedural Manual: Bipolar Disorder Algorithms . Austin,

TX: The Texas Department of State Health Services; 2007.

Goodwin FK, Jamison KR. Medical treatment of hypomania, mania, and mixed states. In: Jamison FK, Jamison

KP, eds. Manic-Depressive Illness: Bipolar Illness and Recurrent Depression. New York, NY: Oxford

University Press; 2007:721. (7)

Goodwin GM et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations

from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30:495–553. (47)

Grunze H et al. The world federation of societies of biological psychiatry (WFSBP) guidelines for the biological

treatment of bipolar disorder. World J Biol Psychiatry. 2013;14:154–219. (50)

Mohammad O, Osser DN. The psychopharmacology algorithm project at the Harvard South Shore Program: an

algorithm for acute mania. Harv Rev Psychiatry. 2014;22(5):274–294. (46)

Sidor MM, Macqueen GM. Antidepressants for the acute treatment of bipolar depression: a systematic review and

meta-analysis. J Clin Psychiatry. 2011;72:156. (174)

Suppes T et al. The Texas implementation of medication algorithms: update to the algorithms for treatment of

bipolar I disorder. J Clin Psychiatry. 2005;66:870.

Yatham LN et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for

Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with

bipolar disorder: update 2009. Bipolar Disord. 2013;15:1–44. (49)

Key Websites

Depression and Bipolar Support Alliance. http://www.dbsalliance.org.

National Alliance on Mental Illness. http://www.nami.org.

National Institute of Mental Health. http://www.nimh.nih.gov.

COMPLETE REFERENCES CHAPTER 87 BIPOLAR

DISORDERS

Wolkenstein L et al. Misdiagnosing bipolar disorder—do clinicians show heuristic biases? J Affect Disord.

2011;130:405.

Evans-Lacko SE et al. Evaluation of guideline-concordant care for bipolar disorder among privately insured youth.

Prim Care Companion J Clin Psychiatry. 2010;12(3).

Judd LL, Akiskal HS. The prevalence and disability of bipolar spectrum disorders in the US population: re-analysis

of the ECA database taking into account subthreshold cases. J Affect Disord. 2003;73:123.

Ferrari AJ et al. Health states for schizophrenia and bipolar disorder within the global burden of disease 2010

study. Popul Health Metr. 2012;10:16.

American Psychiatric Association. Mood disorders. In: American Psychiatric Association, ed. Diagnostic and

Statistical Manual of Mental Disorders. 4th ed. Text Revision. Washington, DC: American Psychiatric

Association; 2000:345.

Merikangas KR et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity

Survey replication. Arch Gen Psychiatry. 2007;64:543.

Goodwin FK, Jamison KR. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression. New York,

NY: Oxford University Press; 2007.

Dilsaver SC. An estimate of the minimum economic burden of bipolar I and II disorders in the United States: 2009.

J Affect Disord. 2011;129:79.

Hirschfeld RM et al. Perceptions and impact of bipolar disorder: how far have we really come? Results of the

national depressive and manic-depressive association 2000 survey of individuals with bipolar disorder. J Clin

Psychiatry. 2003;64:161.

Kupfer DJ et al. Demographic and clinical characteristics of individuals in a bipolar disorder case registry. J Clin

Psychiatry. 2002;63:120.

American Psychiatric Association. Practice guidelines for the treatment of patients with bipolar disorder

(revision). Am J Psychiatry. 2002;159(4 Suppl):1.

American Psychiatric Association. Mood disorders. In: American Psychiatric Association, ed. Diagnostic and

Statistical Manual of Mental Disorders. 5th ed. Text Revision. Washington, DC: American Psychiatric

Association; 2013:123.

Schneck CD et al. Phenomenology of rapid-cycling bipolar disorder: data from the first 500 participants in the

Systematic Treatment Enhancement Program. Am J Psychiatry. 2004;161:1902.

Gitlin MJ et al. Relapse and impairment in bipolar disorder. Am J Psychiatry. 1995;152:1635.

Miklowitz DJ, Ciccetti D. Toward a life span developmental psychopathology perspective on bipolar disorder.

Dev Psychopathol. 2006;18:935–938.

Hallahan B et al. Structural magnetic resonance imaging in bipolar disorder: an international collaborative metaanalysis of individual adult patient data. Biol Psychiatry. 2011;69:326–335.

Martinowich K et al. Bipolar disorder: from genes to behavior pathway. J Clin Invest. 2009;119:726–736.

Beyer JL et al. Stressful life events in older bipolar patients. Int J Geriatr Psychaitry. 2008;23:1271–1275.

Miklowitz DJ, Johnson SL. Social and familial factors in the course of bipolar disorder: basic processes and

relevant interventions. Clin Psychol. 2009;16:281–296.

Goldstein BI et al. Inflammation and the phenomenology, pathophysiology, comorbidity, and treatment of bipolar

disorder: a systematic review of the literature. J Clin Psychiatry. 2009;70:1078–1090.

Drexhage RC et al. The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia

and bipolar disorder. Expert Rev Neurother. 2010;10:59–76.

Gruber J et al. Sleep matters: sleep functioning and course of illness in bipolar disorder. J Affect Disord.

2011;134:416–429.

Faedda GL et al. Clinical risk factors for bipolar disorders: a systematic review of prospective studies. J Affect

Disord. 2014;168:314–321.

Goodwin FK, Jamison KR. Clinical description. In: Jamison FK, Jamison KP, eds. Manic-Depressive Illness:

Bipolar Illness and Recurrent Depression. New York, NY: Oxford University Press; 2007:29.

Goodwin FK, Jamison KR. Conceptualizing manic-depressive illness: the bipolar-unipolar distinction and the

development of the manic-depressive spectrum. In: Goodwin FK, Jamison KR eds. Manic-Depressive Illness

and Recurrent Depression. New York, NY: Oxford University Press; 2007:3.

Baldessarini RJ et al. Onset-age of bipolar disorders at six internationalsites. J Affect Disord. 2010;121:143–146.

Shim IH et al. Mixed-state bipolar I and II depression: time to remission and clinical characteristics. J Affect

Disord. 2014;152–154:340–346.

Undurraga J et al. Suicidal risk factors in bipolar I and II disorder patients. J Clin Psychiatry. 2012;73:778–782.

Salvatore P et al. Weygandt’s on the mixed states of manic-depressive insanity: a translation and commentary on

its significance in the evolution of the concept of bipolar disorder. Harv Rev Psychiatry. 2002;10:255.

Angst F et al. Mortality of patients with mood disorders: follow-up over 34–38 years. J Affect Disord.

2002;68:167.

Laursen TM, Nordentoft M. Heart disease treatment and mortality in schizophrenia and bipolar disorder—

changes in the Danish population between 1994 and 2006. J Psychiatr Res. 2011;45:29–35.

Laursen TM et al. Increased mortality among patients admitted with major psychiatric disorders: a register-based

study comparing mortality in unipolar depressive disorder, bipolar affective disorder, schizoaffective disorder,

and schizophrenia. J Clin Psychiatry. 2007;68:899–907.

Westman J et al. Cardiovascular mortality in bipolar disorder: a population-based cohort study in Sweden. BMJ

Open. 2013;3:e002373, doi: 10.1136/bmjopen-2012-002373.

Marangell LB et al. Prospective predictors of suicide and suicide attempts in 1556 patients with bipolar disorders

followed for up to 2 years. Bipolar Disord. 2006;8:566–575.

Yatham LN et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the

management of patients with bipolar disorder: consensus and controversies. Bipolar Disord. 2005;7(Suppl 3):5.

Nordentoft M et al. Absolute risk of suicide after first hospital contact in mental disorder. Arch Gen Psychiatry.

2011;68:1058–1064.

Hawton K et al. Suicide and attempted suicide in bipolar disorder: a systematic review of risk factors. J Clin

Psychiatry. 2005;66:693.

Cerullo MA, Strakowski SM. The prevalence and significance of substance use disorders in bipolar type I and II

disorder. Subst Abuse Treat Prev Policy. 2007;2:29.

Reiger DA et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the

Epidemiologic Carchment Area (ECA) study. JAMA. 1990;264:2511–2518.

Agrawal A et al. Cannabis involvement in individuals with bipolar disorder. Psychiatry Res. 2011;185:459–461.

Tsai SY et al. Risk factors for completed suicide in bipolar disorder. J Clin Psychiatry. 2002;63:469.

Swann AC. The strong relationship between bipolar and substance-use disorder. Ann N Y Acad Sci.

2010;1187:276.

Woods SW. The economic burden of bipolar disorder. J Clin Psychiatry. 2000;61(Suppl 13):38.

Lish JD et al. The National Depressive and Manic-Depressive Association (DMDA) survey of bipolar members.

J Affect Disord. 1994;31:281.

Judd LL et al. The long-term natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen

Psychiatry. 2002;59:530.

Mohammad O, Osser DN. The psychopharmacology algorithm project at the Harvard South Shore Program: an

algorithm for acute mania. Harv Rev Psychiatry. 2014;22:274–294.

Goodwin GM et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations

from the British Assoication for Psychopharmacology. J Psychopharmacol. 2016;30:495–553.

Ansari A, Osser DN. The psychopharmacology algorithm project at the Harvard South Shore Program: an update

on bipolar depression. Harv Rev Psychiatry. 2010;18:36–55.

Yatham LN et al. Canadian network for mood and anxiety treatments (CANMAT) and internationalsociety for

bipolar disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with

bipolar disorder: update 2013. Bipolar Disord. 2013;15:1–44.

Grunze H et al. The world federation of societies of biological psychiatry (WFSBP) guidelines for the biological

treatment of bipolar disorder. World J Biol Psychiatry. 2013;14:154–219.

Bawa R, Scarff JR. Lurasidone: a new treatment option for bipolar depression – a review. Innov Clin Neurosci.

2015;12:21–23.

Latuda (lurasidone) [package insert]. Marlborough, MA: Sunovion Pharmaceuticals; July 2013.

Peet M, Peters S. Drug-induced mania. Drug Saf. 1995;12:146.

Goldberg JF, Truman CJ. Antidepressant-induced mania: an overview of current controversies. Bipolar Disord.

2003;5:407.

Goren JL et al. Bioavailability and lack of toxicity of S-adenosyl-L-methionine (SAMe) in humans.

Pharmacotherapy. 2004;24:1501.

Moses EL, Mallinger AG. St. John’s wort: three cases of possible mania induction. J Clin Psychopharmacol.

2000;20:115.

Stoll AL et al. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch

Gen Psychiatry. 1999;56:407.

Ogawa N, Ueki H. Secondary mania caused by caffeine. Gen Hosp Psychiatry. 2003;25:138.

Sultzer DL, Cummings JL. Drug-induced mania—causative agents, clinical characteristics and management: a

retrospective analysis of the literature. Med Toxicol Adverse Drug Exp. 1989;4:127.

Padala PR et al. Manic episode during treatment with aripiprazole. Am J Psychiatry. 2007;164:172.

Rachid F et al. Possible induction of mania or hypomania by atypical antipsychotics: an updated review of

reported cases. J Clin Psychiatry. 2004;65:1537.

Abouesh A et al. Antimicrobial-induced mania (antibiomania): a review of spontaneous reports. J Clin

Psychopharmacol. 2002;22:71.

Blanch J et al. Manic syndrome associated with efavirenz overdose. Clin Infect Dis. 2001;33:270.

Jochum T et al. Topiramate induced manic episode. J Neurol Neurosurg Psychiatry. 2002;73:208.

Margolese HC et al. Hypomania induced by adjunctive lamotrigine. Am J Psychiatry. 2003;160:183.

Short C, Cooke L. Hypomania induced by gabapentin. Br J Psychiatry. 1995;166:679.

Watts BV, Grady TA. Tramadol-induced mania. Am J Psychiatry. 1997;154:1624.

Rego MD, Giller EL, Jr. Mania secondary to amantadine treatment of neuroleptic-induced hyperprolactinemia. J

Clin Psychiatry. 1989;50:143.

Price WA, Bielefeld M. Buspirone-induced mania. J Clin Psychopharmacol. 1989;9:150.

Gupta N. Venlafaxine-induced hypomanic switch in bipolar depression. Can J Psychiatry. 2001;46:760.

Bhanji NH et al. Dysphoric mania induced by high-dose mirtazapine: a case for “norepinephrine syndrome”? Int

Clin Psychopharmacol. 2002;17:319.

Zaphiris HA et al. Probable nefazodone-induced mania in a patient with unreported bipolar disorder. Ann Clin

Psychiatry. 1996;8:207.

Benazzi F. Organic hypomania secondary to sibutramin ecitalopram interaction. J Clin Psychiatry. 2002;63:165.

El-Mallakh RS. Bupropion manic induction during euthymia, but not during depression. Bipolar Disord. 2001;3:159.

Baldessarini RJ et al. Patterns of psychotropic drug prescription for US patients with a diagnosis of bipolar

disorders. Psychiatr Serv. 2007;58:85–91.

Gijsman HJ et al. Antidepressants for bipolar depression: a systematic review of randomized, controlled trials. Am

J Psychiatry. 2004;161:1537–1547.

Himmelhoch JM et al. Tranylcypromine versus imipramine in anergic bipolar depression. Am J Psychiatry.

1991;148:910.

Peet M. Induction of mania with selective serotonin reuptake inhibitors and tricyclic antidepressants. Br J

Psychiatry. 1994;164:549.

Leverich GS et al. Risk of switch in mood polarity to hypomania or mania in patients with bipolar depression

during acute and continuation trials of venlafaxine, sertraline, and bupropion as adjuncts to mood stabilizers. Am

J Psychiatry. 2006;163:232.

Mattes JA. Antidepressant-induced rapid cycling: another perspective. Ann Clin Psychiatry. 2006;18:195.

Sachs GS et al. Effectiveness of adjunctive antidepressant treatment for bipolar depression. N Engl J Med.

2007;356:1711–1722.

Altshuler LL et al. Antidepressant-induced mania and cycle acceleration: a controversy revisited. Am J

Psychiatry. 1995;152:1130.

Bowden CL. Valproate. Bipolar Disord. 2003;5:189.

Bowden CL et al. Efficacy of divalproex vs. lithium and placebo in the treatment of mania. JAMA.

1994;271:918–924.

Bowden CL et al. A randomized, placebo-controlled 12-month trial of divalproex and lithium in the treatment of

outpatients with bipolar 1 disorder. Arch Gen Psychiatry. 2000;57:481–489.

Bowden CL et al. Relation of serum valproate concentration to response in mania. Am J Psychiatry.

1996;153:765.

Hirschfeld RM et al. The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex,

lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder. J Clin

Psychiatry. 2003;64:841.

Allen MH et al. Linear relationship of valproate serum concentration to response and optimal serum levels for

acute mania. Am J Psychiatry. 2006;163:272.

Bowden CL et al. A randomized, placebo-controlled, multicenter study of divalproex sodium extended release in

the treatment of acute mania. J Clin Psychiatry. 2006;67:1501.

Smith MC et al. Clinical comparison of extended-release divalproex versus delayed-release divalproex: pooled

data analyses from nine trials. Epilepsy Behav. 2004;5:746.

Depakote (divalproex sodium) [package insert]. North Chicago, IL: AbbVie; February 2016.

Tohen M et al. Olanzapine versus divalproex sodium for the treatment of acute mania and maintenance of

remission: a 47-week study. Am J Psychiatry. 2003;160:1263–1271.

Joffe H et al. Valproate is associated with new-onset oligoamenorrhea with hyperandrogenism in women with

bipolar disorder. Biol Psychiatry. 2006;59:1078.

Mercke Y et al. Hair loss in psychopharmacology. Ann Clin Psychiatry. 2000;12:35.

Kimmel RJ et al. Valproic acid-associated hyperammonemic encephalopathy: a case report from the psychiatric

setting. Int Clin Psychopharmacol. 2005;20:57.

Elgudin L et al. Ammonia induced encephalopathy from valproic acid in a bipolar patient: case report. Int J

Psychiatry Med. 2003;33:91.

Suicidal Behavior and Ideation and Antiepileptic Drugs.

http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm100190.htm

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

127.

.

.

.

Accessed June 15, 2015.

Nasreddine W, Beydoun A. Valproate-induced thrombocytopenia: a prospective monotherapy study. Epilepsia.

2008;49:438.

Acharya S, BusselJB. Hematologic toxicity of sodium valproate. J Pediatr Hematol Oncol. 2000;22:62.

Janicak PG et al. Treatment with mood stabilizers. In: Janicak PG et al. eds. Principles and Practice of

Psychopharmacotherapy. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:369.

Gelenberg AJ, Jefferson JW. Lithium tremor. J Clin Psychiatry. 1995;56:283.

Henry C. Lithium side-effects and predictors of hypothyroidism in patients with bipolar disorder:sex differences.

J Psychiatry Neurosci. 2002;27:104.

Bendz H, Aurell M. Drug-induced diabetes insipidus: incidence, prevention, and management. Drug Saf.

1999;21:449.

Finch CK et al. Treatment of lithium-induced diabetes insipidus with amiloride. Pharmacotherapy. 2003;23:546.

Mellerup ET, Plenge P. The side effects of lithium. Biol Psychiatry. 1990;28:464.

Tredget J et al. Effects of chronic lithium treatment on renal function. J Affect Disord. 2010;126:436.

Lepkifker E et al. Renal insufficiency in long-term lithium treatment. J Clin Psychiatry. 2004;65:850.

Dunner DL. Drug interactions of lithium and other antimanic/mood-stabilizing medications. J Clin Psychiatry.

2003;64(Suppl 5):38.