TREATMENT-RESISTANT BIPOLAR DISORDER
From Individuals With Serious Mental Illness: Optimizing Understanding, Treatment, and Recovery, presented by Loma
Linda University School of Medicine and Patton State Hospital
Michael J. Gitlin, MD, Professor of Psychiatry, The David Geffen School of Medicine at the University of California, Los
Angeles, and Director, Adult Psychiatry Outpatient Mood Disorders Program, UCLA Medical Center, Neuropsychiatric
Institute
Educational Objectives
| The goal of this program is to improve management of treatment-resistant bipolar disorder. After hearing and
assimilating this program, the clinician will be better able to:
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 | 1. Describe how treatment resistance is identified and tracked.
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| 2. Identify first-line treatments commonly used in bipolar disorder.
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| 3. Discuss the potential uses of antipsychotic and anticonvulsive medications in combination therapy.
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| 4. Evaluate the potential usefulness in individual patients of alternative therapies such as thyroid augmentation,
electroconvulsive therapy, omega-3 fatty acids, and calcium channel blockers.
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| 5. Explain the importance of adjunctive psychotherapy and select among available options.
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Faculty Disclosure
In adherence to ACCME guidelines for Commercial Support, the Audio-Digest Foundation requires all faculty and members
of the planning committee to disclose relevant financial relationships within the past 12 months that might create any
personal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality
in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr.
Gitlin is on the Speakers’ Bureau for AstraZeneca, Pfizer, BMS, Cephalon, GlaxoSmithKline, Takeda, Otsuka, and Lilly.
The planning committee reported nothing to disclose.
Acknowledgements
Dr. Gitlin was recorded at Individuals With Serious Mental Illness: Optimizing Understanding, Treatment, and Recovery,
held April 2, 2008, in Loma Linda, CA, and presented by Loma Linda University School of Medicine and Patton
State Hospital. The Audio-Digest Foundation thanks Dr. Gitlin and the sponsors for their cooperation in the production
of this program.
| Introduction: single treatment options often ineffective; more often treated with combination regimens than any other
disorder in psychiatry; limitations of medicines profound and obvious; uses and efficacy of multimodal treatment (medication
plus psychotherapy) increasingly important
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| Defining treatment resistance: specify and track treatment-resistant phase—acute mania, or failure to respond to
antimanic treatments, as opposed to acute bipolar depression, or recurrent breakthrough episodes; conceptualize each
differently; breakthroughs more significant during long-term treatment and maintenance; specify how treatment
failed—determine actual number of failed treatments, both combination and single agent; question whether antidepressants
have destabilized bipolar disorder and induced mood instability; compliance issues—outpatients may not
adhere to treatment plan; recurrent breakthrough episodes may originate from treatment noncompliance, or ineffectual
medication, or both; patient first becomes hypomanic, then stops adhering to medication plan; symptoms increase;
2-pronged process, encompassing noncompliance and breakthrough episodes
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| Established first-line treatments for mania: lithium oldest treatment for acute mania; valproate also approved by
Food and Drug Administration (FDA) for this indication
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| First-generation antipsychotics (FGAs): only chlorpromazine (Thorazine) has FDA indication for mania; however, other
FGAs (eg, haloperidol [Haldol], trifluoperazine, thiothixene [Navane]) work well also
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| Second-generation antipsychotics (SGAs): all except clozapine have FDA indication for acute mania, including risperidone
(Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), and aripiprazole (Abilify)
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| Carbamazepine (eg, Tegretol): established as second-line treatment; recently released in extended-release formula, carbamazepine
ER (Equetro); received FDA approval for acute mania; however, difficult to titrate quickly
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| Established first-line treatments for maintenance: 4 FDA-approved medications; lithium, lamotrigine (Lamictal),
olanzapine, and aripiprazole
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| Lithium: meta-analyses reveal effective episode prevention, especially of relapse; better at preventing mania than depression;
no evidence of reduced efficacy over time
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| Lamotrigine: study that led to FDA indication showed lamotrigine better than placebo at preventing episodes overall; better
at preventing depression than mania; lithium better at preventing mania
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| Pole specificity: avoid using one algorithm for all patients; take history and change algorithm according to dominant pole
for particular patient
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| Olanzapine: study that led to FDA indication showed olanzapine better than placebo at preventing episodes in general;
better at preventing mania than depression; significantly better than lithium at preventing mania
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| Aripiprazole: study that led to FDA indication showed better prevention of mood episodes than placebo (speaker points
out that all prevention occurred in cases of mania); no different from placebo in prevention of depression
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| Divalproex (Depakote): lacks FDA indication for maintenance therapy; study not placebo-controlled; selection criteria
may have influenced study results
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Alternatives to standard treatments
| Other anticonvulsants: small double-blind studies (on acute mania and maintenance), combined phenytoin (Dilantin)
with other medications; fewer relapses reported
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| Oxcarbazepine (Trileptal): conjugate of carbamazepine; recently available as generic; related drugs under development;
clinical study in adolescents negative; some side effect (eg, agranulocytosis, pharmacokinetic interactions) less common
with oxcarbazepine than with carbamazepine; hypernatremia, however, more common with oxcarbazepine; recent naturalistic
study results cast doubt on efficacy; preliminary trials of related drugs emerging as negative
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| Levetiracetam (Keppra): recently released anticonvulsant; no double-blind studies yet; open studies available
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| Zonisamide (Zonegran): recently released anticonvulsant; possibly effective; 1 of 2 medications used with bipolar disorder
that result in weight loss
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| Topiramate (Topamax): well-documented weight loss; 5 double-blind trials for acute mania all negative; possibly effective
for maintenance; drug efficacy—conceptualize treatments for acute phase and preventive maintenance separately;
no study yet available on use for preventive maintenance; not currently recommended for use as solo-agent
preventive long-term mood stabilizer
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| Gabapentin (eg, Neurontin): 2 double-blind studies, including crossover study with mean daily dose of 3941 mg, revealed
no efficacy in any phase; in acute mania study, placebo statistically significantly more effective; possible
anxyiolytic, but lacks true mood-stabilizing properties
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| Tiagabine (Gabitril): recently released anticonvulsant; open studies unimpressive; causes seizures in patients with no
history of epilepsy
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| Combination treatments: polypharmacy common in bipolar disorder; <1 in 5 outpatients with bipolar disorder on only 1
medication; one-third of patients on ≥4 medications; relatively contraindicated combinations—only one (clozapine
combined with carbamazepine); both cause measurable agranulocytosis
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| Most effective combinations: for acute mania, 8 double-blind studies added various SGAs to lithium or divalproex; improved
efficacy; one-quarter more responses to medication; antipsychotic plus lithium or divalproex now standard of
practice for inpatient treatment of acute mania
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| Maintenance studies: dropout rate in 1-yr maintenance studies (65%-70%) exceeds relapse rate; consequently, maintenance
studies difficult to complete; 3-yr study of patients with bipolor disorder type I included 1 yr of lithium, 1 yr
of carbamazepine, and 1 yr of lithium plus carbamazepine; patients on combination therapy did better than those
treated with single agent; especially true of patients with rapid-cycling bipolar disorder, defined as having 4 episodes/yr
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| Other maintenance studies: Brown University study (12 patients) hinted at improved efficacy of lithium plus divalproex;
another study on lithium or divalproex alone for 18 mo; additive effect in maintenance treatment not as effective
as expected; dropout rate 85%
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Other alternatives to standard therapies
| Thyroid augmentation: 2 studies (neither double-blind) used high doses of levothyroxine (L-thyroxine; T4 ), on 11 rapid-
cycling patients; number and amplitude of manic and depressive symptoms decreased, with minimal side effects; dosing
considerations—augmentation doses used to treat depression (0.3 mg/day) much higher than average dose used to
replace functioning thyroid (0.112 mg/day); patient effectively hyperthyroid; such high doses tax patients metabolically;
avoid use in patients at risk for cardiac problems; use with caution in older patients or postmenopausal women
(hyperthyroidism leaches calcium from bones; increases rate of osteoporosis); consider for young, healthy, truly treatment-resistant
patients
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| Clozapine: no double-blind studies; open-label studies positive; in study of 38 treatment-resistant bipolar patients, one-
half randomized to receive clozapine as adjunct to existing medications, and addition clearly beneficial; side effects—
complete blood cell count (CBC) monitoring required; agranulocytosis; weight gain; sedation; orthostatic hypotension;
drug effective but not without issues; worth considering for truly treatment-resistant patients
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| Electroconvulsive therapy (ECT): trial data show efficacy in mania, as for treatment-resistant depression; however, difficulty
obtaining informed consent from patients during manic episodes largely precludes study of ECT use in acute mania
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| Omega-3 fatty acids: studies reveal mixed results; 2 types of omega-3 fatty acids, docosahexaenoic acid (DHA) and
eicosapentaenoic acid (EPA); difficult to determine appropriate type, combination, or ratio needed for treatment;
omega-3 supplements not regulated by FDA, so uniformity of dose difficult to determine; reduction in depression seen
in double-blind study using large (9.6 g) daily dose; no improvement noted in larger multicenter double-blind, add-on
study of 116 participants treated for bipolar depression or on maintenance regimen for rapid cycling
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| Calcium channel blockers: verapamil—early data mixed; uncertain whether drug crosses blood-brain barrier;
nimodipine—also used for subarachnoid bleeding; crosses blood-brain barrier more readily than other agents; older
studies showed promise; warrants further investigation; potential benefits include relatively benign side-effect profile;
largely well tolerated, with some orthostatic hypotension
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| Adjunctive psychotherapies: psychopharmacology alone very limited; series of recent studies reveals effectiveness
of adjunctive psychotherapy
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| Researching multimodal therapy: variations among therapists in therapy methods, including randomly combining cognitive,
behavioral, and other therapies; adjunctive therapy instruction manuals for bipolar disorder standardize practices
and enable accurate study of therapy effectiveness
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| Conducting multimodal therapy: core principles—educate patients about disorder; teach skills to cope with potential
life-stress triggers for mania and depression; reduce sleep deprivation and change sleep patterns to avoid triggers for
mania and hypomania; encourage compliance with treatment plans
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| Family-focused treatment (FFT): adapts behavioral family management strategies used for schizophrenia for use in families
of patients with bipolar disorder; focuses on assessment and education; relapse drill—family and household preparation
and plan for action in event of relapse; enhanced household communication—decrease high expressed emotion,
including criticism; encourage parental comments on behavior, not character; data reveal benefits of FFT; 1-yr follow-
up showed significantly fewer relapses, especially in depression; effect greatest in patients and families prone to high
expressed emotion and intrusiveness within family structure; better compliance and fewer episodes sustained for 2 yr;
consider FFT for patients in intact families
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| Cognitive therapy: 1-yr follow-up of British study with 103 participants and 18 sessions revealed fewer relapses in each
pole (mania and depression) and fewer hospitalizations
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| Group psychoeducation: inexpensive and effective therapy; group meeting focuses on education; beneficial effects examined
at 4 mo, 2 yr, and 5 yr; cost comparable to one-day hospital stay
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| Interpersonal and social rhythm therapy (IPSRT): classic interpersonal therapy; tracks relationship between life events
and episodes; examines relationships and social rhythms; less beneficial than other therapies
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| Conclusions: develop better strategies to address treatment-resistant bipolar disorder by further studying dominant form
of treatment (ie, combination therapy); focus on improving patient compliance; adapt adjunctive psychotherapy models
that reflect requirements and patterns of real-world work; better strategies expected within 5 yr
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Further questions
| Thyroid augmentation at lower doses of T4 : results unknown; studies have explored only high-dose thyroid augmentation
in bipolar patients
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| Paliperidone (Invega): may be combined with divalproex; efficacy and side effects similar to any other SGA or other derivative
or metabolite of risperidone
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| Carbamazepine vs oxycarbazepine: more data available with carbamazepine; oxycarbazepine better tolerated and less
complex medication; no CBC required; no agranulocytosis
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| Role of monoamine oxidase inhibitors (MAOIs) in treating bipolar mixed states: classic mixed state variation on mania,
not variation on depression; treatments for mixed state usually antipsychotics, lithium, and anticonvulsants; avoidance
of antidepressants recommended, even though mixed state may include dysphoria; recently noted state (not yet defined
in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV]) possibly mixed depression rather
than mixed mania; patient exhibits irritability, agitation, and racing thoughts along with depression; antidepressants
possibly helpful
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| Topiramate: causes metabolic acidosis in some patients; unclear whether blood chemistry panels routinely necessary
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| Oxcarbazepine and hypernatremia: develops in 2% to 5% of patients; more likely in older patients; consider checking serum
sodium as patients age; early symptoms (eg, fatigue, mild confusion) difficult to distinguish from other common
side effects
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| Role of clonidine (Catapres) as add-on: infrequently used; studied in 1980s; patients disliked; very sedating and orthostatic;
harder to use in adults with bipolar disorder than in adolescents and children with attention-deficit disorder (ADD)
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| Manic patients: some continue use of SGAs plus lithium or divalproex, even after significant period of stabilization; if
patient complains of medication burden, discontinue excess medications gradually to encourage compliance; retain essential
and effective treatments
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| Adding clozapine: after improvement noted, continue other medications for 1 yr; slowly taper lithium, valproate, or others
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| Medication use during first trimester of pregnancy: complicated issue; SGAs probably safest antimania agent; lithium
next safest; best to avoid divalproex and carbamazepine during first trimester
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Suggested Reading
Bota RG: Therapeutic dilemmas in treatment-resistant bipolar patients. South Med J 101:584, 2008; Dratcu L: Clozapine-resistant
psychosis, smoking, and caffeine: managing the neglected effects of substances that our patients consume every
day. Am J Ther 14:314, 2007; Gitlin M: Treatment-resistant bipolar disorder. Mol Psychiatry 11:227, 2006;
González-Pinto A: Epidemiology, diagnosis and management of mixed mania. CNS Drugs 21:611, 2007; Howland
RH: Lithium: underappreciated and underused? J Psychosoc Nurs Ment Health Serv 45:13, 2007; Lee JH: The effect of
anxiety disorder comorbidity on treatment resistant bipolar disorders. Depress Anxiety 25: 91, 2008; Lin PY: A meta-analytic
review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry
68:1056, 2007; Lokjo D: L-thyroxine augmentation of serotonergic antidepressants in female patients with refractory depression.
J Affect Disord 103: 253, 2007; Majczenko TG: Failure of filgrastim to prevent severe clozapine-induced
agranulocytosis. South Med J 101:639, 2008; Nieto E: Oxcarbazepine in the bipolar and schizoaffective disorders. Actas
Esp Psiquiatr 36:28, 2008; Owen C: The role of fatty acids in the development and treatment of mood disorders. Curr
Opin Psychiatry 21:19, 2008; Papadimitriou GN: Non-pharmacological treatments in the management of rapid cycling
bipolar disorder. J Affect Disord 98:1, 2007; Rowe DL: Off-label prescription of quetiapine in psychiatric disorders. Expert
Rev Neurother 7:841, 2007; Sienaert P: Electroconvulsive therapy: an effective therapy of medication-resistant bipolar
disorder. Bipolar Disord 8:307, 2006; Soares-Weiser K: A systematic review and economic model of the clinical
effectiveness and cost-effectiveness of interventions for preventing relapse in people with bipolar disorder. Health Technol
Assess 11:iii, 2007.
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