DIAGNOSIS AND TREATMENT OF THE BIPOLAR SPECTRUM
From 2006 Psychopharmacology Academy, presented by the Neuroscience Education Institute
Ronnie G. Swift, MD, Professor and Associate Chairman, Department of Psychiatry, New York Medical College;
Chief of Psychiatry and Behavioral Health, Generations+/Northern Manhattan Health Network of the New York City
Health & Hospitals Corporation; Chief of Psychiatry and Associate Medical Director, Metropolitan Hospital
Center; and Interim Chief of Psychiatry, Lincoln Medical and Health Center, New York, NY
| Introduction: most patients with bipolar disorder present with depression; they spend far more time being depressed
than hypomanic, manic, or cycling; because percentage of time bipolar patients spend in hypomanic
phase small, often takes many years for correct diagnosis to be made; history important in differentiating bipolar
from unipolar depression, and especially important to get history from collateral people because patients
in hypomanic phase often “fine with their symptoms it’s everybody around them who recognizes how impaired
they are”; patient may have little or no insight into his or her own impairment; patients report depression
because they feel uncomfortable with it, but they often do not report hypomania because they think it is
just “good mood”
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| Hypomania: mood elevation not necessary for hypomania; “you can just have overactivity and be hypomanic”;
look for changes in personality (“the person who all of a sudden is making lists and doing this
and that and then it stops”); when hypomanic, patient may not remember symptoms he or she experienced
in depressive phase
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| Asking the right questions: best predictor of bipolar disorder is early age of onset and much time spent being
ill; ask about hypomanic symptoms right before or right after depressive episode; ask whether others have
mentioned noticing bipolar symptoms in patient; make questions as specific as possible; inquire about overactivity;
describe symptoms of mania (patient may not know) and inquire about out-of-character impulsive behaviors
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| History: explore family history, treatment history, and history of medication response (many medications,
including antidepressants, can induce hypomania or mania); history of substance of abuse causing switch to
mania suggestive of patient’s having bipolar disorder
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| Education: “information sharing is a two-way street”; educate patient and family as to what to expect; ask
them to call as soon as they notice any behavior suggestive of bipolar episode; advise them that bipolar disorder
is progressive
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| Bipolar vs unipolar depression: in survey of 600 people with bipolar disorder, >33% sought help within
first year, but 69% not diagnosed as bipolar; respondents had seen average of 4 physicians, and 33% did
not receive bipolar diagnosis for 10 yr; were they misdiagnosed? or did they have no early symptoms that
suggested bipolar disorder?
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| Life charting: provides patient and family with insight into patient’s symptoms; can help patient to determine
what stressors trigger bipolar episode, to assess whether illness progressing, and to evaluate treatment
response
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| Making diagnosis: many patients with bipolar disorder never have had full-blown manic episode; some
have poor recollection of past mood states; many like their hypomania but dislike their depression; Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) says patient must
have symptoms for 4 days to make diagnosis, but no data to support that figure (which was arbitrarily determined)
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| Monotherapy with lithium: good evidence to show lithium works in acute phase of mania and hypomania
and as maintenance therapy; shown to reduce suicide risk; disadvantages—necessity for blood monitoring
(although new fingerstick method may be more acceptable to some patients than having blood drawn with
needle); narrow therapeutic index; possibility of causing congenital malformations (controversial); possibility
that patient taken off lithium (such as parturient) may not respond if it is restarted; tips for use—use
lowest dose associated with therapeutic response; better tolerated during acute phase than during maintenance;
when used for maintenance, consider once-a-day dosing at night (eliminates cognitive dulling); controlled-release
formulations may reduce peak blood levels and side effects; generic forms of lithium can be
“profoundly different in bioavailability” as well as in side effects; dose usually 300 mg 2 to 3 times/day up
to 1800 mg/day; extended-release formulations “a good idea if the insurance company will pay for it”
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| Reducing suicide risk and treating acute mania: lithium and clozapine (Clozaril) only drugs shown to reduce
suicide risk; all atypical antipsychotic medications work as monotherapy in acute mania; if lithium
started while patient in hospital, atypical antipsychotic probably will need to be started because most insurance
companies do not allow long enough inpatient stays for lithium to reach therapeutic levels
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 | Acute mania: ziprasidone—20-mg dose starts to calm acute agitation within 15 min; does not cause prolonged
sedation (patient usually “up and moving in <2 hr but not in that aggressive, agitated fashion”);
single dose remains effective for 4 hr; olanzapine—intramuscular (IM) formulation better than lorazepam
for acute agitation; works in as little as 15 to 30 min; efficacy not necessarily dependent on antipsychotic
effect; calms patient without excess sedation; initial dose 10 mg IM, except in elderly, in whom dose
should be smaller; quetiapine—in depressive phase, not much difference between 300-mg dose and 600-
mg dose, but in manic phase, many patients need more than 300 mg; olanzapine-fluoxetine combination
(Symbyax)—better than olanzapine alone
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| Dysphoric mania: loosely defined as score >2 on at least 2 parameters (dysphoric mood, worry, self-reproach,
negative self-evaluation, discouragement, suicidal tendencies, fatigue, and loss of interest); in
study, overall rate of relapse lower with olanzapine; data good for long-term management with ziprasidone
and aripiprazole
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| Psychotic symptoms: study showed that treating physicians estimated that 50% of their patients had psychotic
symptoms, but when patients of those physicians asked, 90% reported psychotic symptoms; difference
explained by differing definitions of “psychotic”; one definition requires hallucinations and delusions,
while another requires only “simple break in reality testing”
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| Tolerability of atypical antipsychotic medications: many patients gain weight on atypical antipsychotic
and anticonvulsant drugs, and no way of predicting which patients will have problems; speaker asks whether
family member has had good response on some medication and uses that information to select first-line drug;
patients discontinue medications for many reasons and need to be educated about compliance; if patient feels
well, he or she may think medication no longer needed; advise patient that bipolar disorder not like pneumonia,
where medications taken for a while and disease cured, but more like diabetes, where treatment must continue
for long term; use psychotherapeutic skills to educate patient and family
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| Monotherapy with atypical antipsychotics: quetiapine (Seroquel) has best evidence of efficacy as monotherapy,
but other atypical antipsychotics can be used
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| Dosing: aripiprazole— can be dosed as high as 30 mg, but may need to be limited to 5 to 10 mg to avoid activation
and akathisia; start with low dose and increase slowly; olanzapine—some patients benefit from
≥30 mg; Zydis formulation dissolves in mouth, cannot be spit at people; IM formulation can be started in
emergency department, switched to oral or Zydis formulation when patient admitted to hospital;
quetiapine—at low doses, acts as sedative hypnotic; acute mania can require doses as high as 600 mg;
depression may require 300 mg; speaker has used as high as 1200 mg in patients with substance-induced
psychosis or mania; risperidone—dose range 2 to 6 mg; can cause elevation of prolactin; best not to use if
patient has personal or family history of prolactin-sensitive breast cancer; Risperdal Consta is long-acting
depot formulation; ziprasidone—dose range 120 to 160 mg; low dose can be extremely activating,
and speaker advises raising dose quickly; IM formulation available
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| Divalproex: onset of action occurs within 5 days, especially with oral loading; generic formulations highly
variable in side-effect profiles and in bioavailability; starting dose 1000 mg/day, can be increased rapidly;
different ethnic groups metabolize divalproex at different rates; slow metabolizers have higher blood levels
at lower dose, and rapid metabolizers have opposite; risk for hepatotoxicity greatest in children ≤2 yr of
age, decreases in progressively older age groups; if given in pregnancy, may produce neural tube defects in
fetus
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| Lamotrigine: efficacious at 200 mg; speaker finds it especially useful in developmentally disabled patients
with comorbid psychiatric disorder; helps calm verbal and physical aggressivity; approved for maintenance
therapy in bipolar I disorder, and shown to be significantly superior to placebo in preventing recurrence
of mood episodes; unclear whether it is as efficacious in managing acute mania; in maintenance
therapy in bipolar II, superior to placebo in preventing relapse for 6 mo; speaker finds fewer side effects
in patients taking lamotrigine; possible serious side effects include rash that may progress to Stevens-
Johnson syndrome and agranulocytosis; therapeutic dose as monotherapy 100 to 200 mg; levels affected
by divalproex and other anticonvulsants, and slow titration of lamotrigine necessary
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| Medication combinations: choose medications that have different modes of action to obtain benefits of
both; combinations that have not been studied but are rational include lithium and carbamazepine and
aripiprazole and lamotrigine
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| Evidence-based combinations: lithium with any atypical antipsychotic, especially olanzapine, risperidone,
or quetiapine; divalproex with any atypical antipsychotic, especially olanzapine, risperidone, or quetiapine;
olanzapine-fluoxetine combination
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| Instruments for measuring: magnitude of effect for above combinations may differ with different instruments,
but all instruments agree combinations better than placebo
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| Guidelines for combining divalproex and lamotrigine: divalproex inhibits metabolism of lamotrigine,
necessitating reduction in lamotrigine dose (ultimate dose should be ≈50% of that of lamotrigine as monotherapy);
if divalproex stopped, remember to increase dose of lamotrigine
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| Multidrug therapy: generally the rule in bipolar disorder; some patients may need up to 5 medications;
medications can be combined rationally if they have different mechanisms of action
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Educational Objectives
| The goal of this program is to educate the listener about the diagnosis and treatment of the bipolar spectrum. After
hearing and assimilating this program, the clinician will be better able to:
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| 1. Explain why bipolar illness is considered to be a spectrum disease.
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| 2. Ask the right questions to elicit a diagnosis of bipolar disorder.
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| 3. Discuss which medications have been shown to reduce suicide risk in patients with bipolar disorder.
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| 4. Describe the best medications for monotherapy in bipolar disorder.
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| 5. Discuss the best medication combinations for treating bipolar disorder.
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Discussed on This Program
Aripiprazole [Abilify]
Carbamazepine [Carbatrol, Epitol, Tegretol]
Clozapine [Clozaril, FazaClo]
Haloperidol [Haldol]
Lamotrigine [Lamictal]
Lithium (several formulations and trade names)
Lorazepam [Ativan, Lorazepam Intensol]
Olanzapine [Zyprexa]
Olanzapine and fluoxetine HCl [Symbyax]
Quetiapine fumarate [Seroquel]
Risperidone [Risperdal]
Valproic acid [Depacon, Depakene, Depakote]
Ziprasidone HCl [Geodon]
Suggested Reading
Altamura AC: Bipolar spectrum and drug addiction. J Affect Disord Oct 4, 2006 [Epub ahead of print]; Bahk
WM et al: Topiramate and divalproex in combination with risperidone for acute mania: a randomized open-label
study. Prog Neuropsychopharmacol Biol Psychiatry 29:115, 2005; Benazzi F: The continuum/spectrum concept of
mood disorders: is mixed depression the basic link? Eur Arch Psychiatry Clin Neurosci Sep 7, 2006 [Epub ahead of
print]; Bowden CL: Atypical antipsychotic augmentation of mood stabilizer therapy in bipolar disorder. J Clin Psychiatry
66(Suppl 3):12, 2005; Brugue E, Vieta E: Atypical antipsychotics in bipolar depression: Neurobiological
basis and clinical implications. Prog Neuropsychopharmacol Biol Psychiatry Jul 27, 2006 [Epub ahead of print];
Chengappa KN, Suppes T, Berk M: Treatment of bipolar mania with atypical antipsychotics. Expert Rev Neurother
4(6 Suppl 2):S17, 2004; Cipriani A, Rendell JM, Geddes JR: Haloperidol alone or in combination for
acute mania. Cochrane Database Syst Rev 3:CD004362, 2006; Corya SA et al: A 24-week open-label extension
study of olanzapine-fluoxetine combination and olanzapine monotherapy in the treatment of bipolar depression. J
Clin Psychiatry 67:798, 2006; Dando TM, Keating GM: Spotlight on quetiapine in acute mania and depression
associated with bipolar disorder. CNS Drugs 20:429, 2006; Gonzalez-Pinto A et al: Suicidal risk in bipolar I disorder
patients and adherence to long-term lithium treatment. Bipolar Disord 8:618, 2006; Houston JP et al: Reduced
suicidal ideation in bipolar I disorder mixed-episode patients in a placebo-controlled trial of olanzapine
combined with lithium or divalproex. J Clin Psychiatry 67:1246, 2006; Keck PE Jr: Long-term management strategies
to achieve optimal function in patients with bipolar disorder. J Clin Psychiatry 67(Suppl 9):19, 2006; Lin D,
Mok H, Yatham LN: Polytherapy in bipolar disorder. CNS Drugs 20:29, 2006; Nasrallah HA, Ketter TA,
Kalali AH: Carbamazepine and valproate for the treatment of bipolar disorder: a review of the literature. J Affect
Disord 95:69, 2006; Nguyen LN, Guthrie SK: Risperidone treatment of bipolar mania. Ann Pharmacother
40:674, 2006; Patel NC, Keck PE Jr: Ziprasidone: efficacy and safety in patients with bipolar disorder. Expert
Rev Neurother 6:1129, 2006; Schatzberg AF: Employing pharmacologic treatment of bipolar disorder to greatest
effect. J Clin Psychiatry 65(Suppl 15):15, 2004; Surja AA, Tamas RL, El-Mallakh RS: Antipsychotic medications
in the treatment of bipolar disorder. Curr Drug Targets 7:1217, 2006; Thase ME: Bipolar depression: issues
in diagnosis and treatment. Harv Rev Psychiatry 13:257, 2005; Tohen M et al: Relapse prevention in bipolar I disorder:
18-month comparison of olanzapine plus mood stabiliser v. mood stabiliser alone. Br J Psychiatry 184:337,
2004; Vieta E: Maintenance therapy for bipolar disorder: current and future management options. Expert Rev Neurother
4(6 Suppl 2):S35, 2004; Yatham LN: Atypical antipsychotics for bipolar disorder. Psychiatr Clin North Am
28:325, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
Dr. Swift reported nothing to disclose.
Dr. Swift was recorded at 2006 Psychopharmacology Academy, held June 10-11, 2006, in San Francisco, CA, and
sponsored by the Neuroscience Education Institute. The Audio-Digest Foundation thanks Dr. Swift and NEI for their
cooperation in the production of this program.
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