Managementof Bipolar Disorder
`
`KIM S. GRISWOLD, M.D., M.P.H., and LINDA F, PESSAR, M.D.
`State University of New Yorkat Buffalo, Buffalo, New York
`
`Bipolar disorder most commonly is diagnosed in persons between 18 and 24
`years of age. The clinical presentations of this disorder are broad and include
`mania, hypomania and psychosis. Frequently associated comorbid conditions
`include substance abuse and anxiety disorders. Patients with acute mania must
`be evaluated urgently. Effective mood stabilizers include lithium, valproic acid
`and carbamazepine. A comprehensive management program,including collab-
`oration between the patient's family physician and psychiatrist, should be
`implemented to optimize medical care. (Am Fam Physician 2000;62:1343-53,
`1357-8.)
`
`on page 1357.
`
`Ca patient informa-
`tion handout on bipo-
`far disorder, written by
`the authors of this
`article, is provided
`
`faa This article
`exemplifies the AAFP
`2000 AnnualClinical
`Focus on mental health.
`
`ipolar disorder is characterized by
`variations in mood, from elation
`and/or irritability to depression.
`This disorder can cause majordis-
`ruptions in family, social and
`occupational life, Bipolar I disorderis defined as
`episodes offull mania alternating with episodes
`
`
`
`TABLE 1
`Causes of Secondary Mania
`
`Substance abuse
`
`Amphetamines
`Caffeine
`Cocaine
`
`Over-the-counterdietpills (e.g.,
`phenylpropanolamine)
`Methylphenidate(Ritalin)
`
`Drug withdrawalstates
`Ethanol
`Monoamine oxidase inhibitors
`
`Sympathomimetic agents
`Tricyclic antidepressants
`
`Toxic metabolic states
`
`Hyperthyroidism
`Electrolyte abnormalities
`Central nervous system disorders
`Multiple sclerosis
`Brain tumor
`
`Sleep deprivation
`Structural damageto right
`(non-dominant) hemisphere
`Temporal lobe (complex partial)
`seizures
`
`Infections
`
`Therapeutic agents
`Isoniazid
`Levodopa
`Monoamine oxidase inhibitors
`Steroids
`Tricyclic antidepressants
`
`Encephalitis
`Syphilis of the central nervous system
`Sepsis
`
`Adapted with permission from Krauthammer C, Klerman GL. Secondary mania.
`Arch Gen Psych 1978;35:1333-9, and Cassem NH. Depression. In: Hackett TP
`Cassem NH, eds. Massachusetts General Hospital handbook of general hospital
`psychiatry. 2d ed. Littleton, Mass.: PSG, 1987:227-60.
`
`of major depression. Patients with mania often
`exhibit disregard for danger and engagein high-
`risk behaviors such as promiscuous sexual
`activity, increased spending, violence, substance
`abuse and driving while intoxicated.
`Bipolar
`II disorder is characterized by
`recurrent episodes of major depression and
`hypomania. Hypomania is manifested by an
`elevated and expansive mood. The behaviors
`characteristic of hypomania are similar to
`those of mania but without gross lapses of
`impulse and judgment. Hypomania does not
`cause impairmentof function and mayactu-
`ally enhance function in the short term.
`Bipolar | disorder is typically diagnosed
`when patients are in their early 20s. Manic
`symptomscanrapidly escalate over a period
`of days and frequently follow psychosocial
`stressors. Some patients initially seek treat-
`ment
`for depression. Other patients may
`appear irritable, disorganized or psychotic.
`Differentiating true mania from maniaresult-
`ing from secondary causes can be challenging
`(Table 1).'*
`Bipolar II disorder typically is brought to
`medical attention when the patient
`is
`depressed. A careful history will usually illu-
`minate the diagnosis. Some depressed patients
`exhibit hypomania when given antidepres-
`sants.* This variation is sometimes referred to
`as bipolarIII disorder. Thecriteria for major
`depressive episode and manic episode, as
`described in the Diagnostic and Statistical
`Manual of Mental Disorders, 4th ed. (DSM-
`IV), are summarized in Table 2.4
`
`SEPTEMBER 15, 2000 / VOLUME 62, NUMBER 6
`
`www.aafp.org/afp
`
`AMERICAN FAMILY PHYSICIAN
`
`1343
`
`1 of 11
`
`Alkermes, Ex. 1027
`
`1 of 11
`
`Alkermes, Ex. 1027
`
`

`

`TABLE 2
`Criteria for Major Depressive Episode and Manic Episode
`
`Major depressive episode
`Five or more of the following symptoms have been present during the samme 2-week period and represent a change from previous
`functioning; at least one of the symptomsis either (1) depressed mood or (2) loss of interest or pleasure.
`1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or
`observation madeby others (e.g., appears tearful). Note: In children and adolescents, can be irritable mood.
`2. Markedly diminished interest or pleasure in all, or almostall, activities most of the day, nearly every day (as indicated by either
`subjective account or observation madeby others)
`3. Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month),
`or decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains.
`4. Insomnia or hypersomnia nearly every day
`5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness
`or being slowed down)
`6. Fatigue or loss of energy nearly every day
`7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach
`or guilt about beingsick)
`8. Diminished ability to think or concentrate, or indeciseveness, nearly every day (either by subjective account or as observed
`by others)
`9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a
`specific plan for committing suicide
`Manic episode
`A. A distinct period of abnormally and persistently elevated, expansive , orirritable mood, lasting at least 1 week (or any duration
`if hospitalization is necessary)
`B. During the period of mooddisturbance, three (or more) of the following symptoms have persisted (four if the mood is onlyirritable)
`and have beenpresentto a significant degree:
`. Inflated self-esteem or grandiosity
`. Decreased need forsleep (e.g., feels rested after only 3 hours of sleep)
`. More talkative than usual or pressure to keep talking
`. Flight of ideas or subjective experience that thoughts are racing
`. Distractibility (i.e., attention too easily drawn to unimportant orirrelevant external stimuli)
`. Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation
`. Excessive involvement in pleasurable activities that have a high potential for painful consequences(e.g., engaging in unrestrained
`buying sprees, sexual indiscretions, or foolish business investments)
`
`
`
`anufbwnDN=
`
`Reprinted with permission from American Psychiatric Association. Diagnostic andstatistical manual of mental disorders. 4th ed. Wash-
`ington, D.C.: American Psychiatric Association, 1994:327,332. Copyright 1994.
`
`
`
`Epidemiology
`Thelifetime prevalence of bipolar disorder
`The Authors
`is 1 percent, which compares toalifetime
`
`KIM S. GRISWOLD, M.D., M.PH., is assistant professor of farnily medicine and psychiatry
`prevalence of 6 percent for unipolar depres-
`in the Department of Family Medicine at the State University of New York (SUNY) at Buf-
`sion.’ The prevalence of bipolar disorder does
`falo School of Medicine and Biomedical Sciences. She received a master’s degree in pub-
`lic health from Yale University, New Haven, Conn., and completed a faculty development
`notdiffer in males and females.® The disorder
`fellowship in primary care at Michigan State University College of Human Medicine, East
`affects personsofall ages. The epidemiologic
`Lansing. After graduating from the SUNY-Buffalo School of Medicine and BiomedicalSci-
`catchment area study revealed the highest
`ences, she completed a family practice residency at Buffalo (N.Y.) General Hospital.
`prevalence in the 18-to-24-year age group.’ In
`somepatients, however, bipolar disorder does
`not become manifest until patients are older.
`One study reported new-onset bipolar disor-
`der in patients older than 60 years.®
`is
`The incidence of bipolar disorder
`increased in first-degree relatives of persons
`with the disorder, as is the incidence of other
`
`is a psychiatrist and associate professor ofclinical psychiatry
`LINDA F. PESSAR, M.D.,
`and family medicine at SUNY~Buffalo School of Medicine and Biomedical Sciences,
`where sheis also director of medical student education in psychiatry. She received a
`medical degree from Columbia University College of Physicians and Surgeons, New
`York City, and completed a psychiatry residency at New York State Psychiatric Insti-
`tute/Columbia Presbyterian Medical Center, New York City.
`
`Address correspondence to Kim S. Griswold, M.D., M.PH., Department of Family Med-
`icine, State University of New York at Buffalo, Center for Urban Research in Primary
`Care, 135 Grant St, Buffalo, NY 14213. Reprints are not available from the authors.
`
`1344
`
`AMERICAN FAMILY PHYSICIAN
`
`www.aafp.org/afp
`
`VOLUME 62, NUMBER 6 / SEPTEMBER 15, 2000
`
`2 of 11
`
`Alkermes, Ex. 1027
`
`2 of 11
`
`Alkermes, Ex. 1027
`
`

`

`Bipolar Disorder
`
`If agitation is prominent in bipolar disorder, hypomanic symp-
`toms may be misunderstood as reflecting an anxiety state.
`
`family physician and her psychiatrist. A
`patient with bipolar disorder should be
`encouraged to plan pregnancy so that the
`dosage of her psychiatric medication can be
`slowly tapered. Therisk of relapse is increased
`with abrupt discontinuation.’®
`Relapse during pregnancy must betreated
`aggressively with moodstabilizers. The patient
`should be admitted to the hospital. If lithium
`therapy is required,
`the patient should be
`counseled regarding the increasedrisk ofcar-
`diovascular malformations in fetuses exposed
`to lithium. Breast-feeding during lithium
`therapy is discouraged because lithium is
`excreted in breast milk.'*
`During the postpartum period, worsening
`of affective symptoms may occur, including
`rapid cycling, which is sometimes refractory
`to drug therapy.'? Women who have worsen-
`ing of symptoms postpartum may have an
`increased risk of recurrence.
`
`Comorbid Conditions
`
`Studies of primary care patients with major
`depressive disorders have demonstrated a ten-
`dency toward certain comorbid conditions. In
`one study,!® more than 42 percent of patients
`meeting thecriteria for a major depressive dis-
`order (including bipolar disorder) had life-
`time histories of substance abuse. In another
`study,” the frequency of substance abuse was
`39 percent in adolescents who had symptoms
`of bipolar disorder. Another study” revealed a
`high prevalence of moderate to severe anxiety
`disorders in association with bipolar disorder,
`as well as a high prevalence of psychosocial
`morbidity.
`While manypatients with bipolar disorder
`show gradual improvementin thefirst several
`years after diagnosis, a substantial subgroup
`experiences poor adjustment in one or more
`
`mood disorders.? One study revealed a 13 per-
`centrisk of bipolar disorder amongoffspring of
`personswith the disorder.'° The risk of unipo-
`lar depression was 15 percent, and therisk of
`schizoaffective disorder was 1 percent.'° The
`mode of inheritance remains unclear, and no
`algorithm exists to predict the risk of bipolar
`disorder.'! Because of the familial association,
`genetic counseling should be offered to patients
`and their families as part of comprehensive
`educational and supportive approaches.
`
`Clinical Presentations
`
`Patients with symptoms of a mood disorder
`often do not meet thefull criteria for bipolar
`disorder. Many patients with bipolar disorder
`are diagnosed as having depression.If agitation
`is prominent, hypomanic symptoms may be
`misunderstood as representing an anxiety state.
`Accurate diagnosis of bipolar disorder requires
`obtaining a comprehensive psychiatric history.
`
`CHILDREN
`
`Hyperactivity is the most common behav-
`ioral manifestation of mania in children.”
`Manic children may exhibit
`irritability or
`temper tantrums.'? The differential psychi-
`atric diagnoses include attention-deficit/
`hyperactivity disorder, conduct disorder and
`schizophrenia.'*
`
`ADOLESCENTS
`
`Manic symptomsin adolescents are similar
`to those in adults. Florid psychosis can be a
`presentation of bipolar disorder in adoles-
`cents. Included in the differential diagnosis of
`mania in adolescents are substance abuse and
`schizophrenia, which may be challenging to
`distinguish from bipolar disorder. The normal
`risk-taking behavior in some adolescents must
`be distinguished from the reckless nature of
`manic symptoms.
`
`DURING PREGNANCY
`
`The course ofbipolar disorder during preg-
`nancy is variable. Management requires sus-
`tained collaboration between the patient’s
`
`SEPTEMBER 15, 2000 / VOLUME 62, NUMBER 6
`
`www.aatp.org/afp
`
`AMERICAN FAMILY PHYSICIAN
`
`1345
`
`3 of 11
`
`Alkermes, Ex. 1027
`
`3 of 11
`
`Alkermes, Ex. 1027
`
`

`

`Patients presenting with acute mania should be evaluated
`urgently; appropriate transportation of the patient from the
`office to the hospital must be arranged.
`
`areas of functioning.?' In a study of psychi-
`atric patients who were evaluated 30 to 40
`yearsafter the index hospitalization for mania,
`24 percent of the sample was considered to be
`occupationally incapacitated.”
`
`Treatment
`URGENT AND EMERGENT
`
`If a patient with symptomsof acute mania
`presents to the office, a psychiatrist should be
`consulted,and the patient should be evaluated
`urgently. The family physician must know the
`legal requirements in the community for
`transferring a patient with acute mania from
`the office to the hospital. Often, police must be
`involved. It is inappropriate to expect family
`members to transport the patient from the
`office to the hospital, because family members
`may not appreciate the irrationality of manic
`thinking and the unpredictability of manic
`behavior.
`The family physician and psychiatrist have
`the responsibility to inform, educate and sup-
`port family membersin terms of the possible
`need for the family to petition the court for
`the patient’s admissionto a psychiatric unit.It
`is important to recognize, andto try to allay,
`the guilt and regret family membersoften feel
`in these circumstances.
`Patients with newly diagnosed bipolar dis-
`order require a medical evaluation along with
`a psychiatric evaluation. Table 3”lists the rec-
`ommendedlaboratory tests for patients eval-
`uated on an inpatient or an outpatient basis.
`Computed tomography or magnetic reso-
`nance imaging and electroencephalography
`are second-line options in the evaluation of
`treatment-resistant patients. These studies are
`not routinely required without a specific clin-
`ical reason. Similarly, the need for electrocar-
`
`diography in patients younger than 40 years
`rests with the clinician’s judgment.
`If necessary, and if the patient has been in
`good general health, moodstabilizers, as well
`as other drugs used in the treatment of bipo-
`lar disorder, can be started before the test
`results are available.If the need to begin treat-
`mentis urgent, medication can be given even
`before laboratory specimensare obtained.
`
`COLLABORATIVE ONGOING CARE
`
`Given the chronic nature of bipolar disor-
`der and its impact on the entire family, it is
`
`TABLE 3
`
`Laboratory Evaluation of Patients
`Presenting with Bipolar Disorder
`
`Inpatient
`Complete physical examination
`Serum levels of lithium, valproic acid (Depakene),
`carbamazepine (Tegretol) and selected tricyclic
`antidepressants (if relevant)
`Thyroid function tests
`Complete blood count and general chemistry
`screening
`Urinalysis if lithium therapyis initiated
`Electrocardiography in patients older than 40 years
`Urine toxicology for substance abuse
`Pregnancy test (if relevant)
`Outpatient
`Complete physical examination
`Serum levels of lithium, valproic acid,
`carbamazepine and selected tricyclic
`antidepressants (if relevant)
`Thyroid function tests
`Complete blood count and general chemistry
`screening
`Urinalysis if lithium therapyis initiated
`Pregnancytest (if relevant)
`Second-line tests: urine toxicology for substance
`abuse and electrocardiography in patients older
`than 40 years
`
`Adapted with permission from Steering Committee.
`Treatment of bipolar disorder. The Expert Consensus
`Guideline Series.
`J Clin Psychiatry 1996,;57(suppl
`12A):3-88.
`
`
`1346
`
`AMERICAN FAMILY PHYSICIAN
`
`www.aafp.org/afp
`
`VOLUME 62, NUMBER 6 / SEPTEMBER 15, 2000
`
`4 of 11
`
`Alkermes, Ex. 1027
`
`4 of 11
`
`Alkermes, Ex. 1027
`
`

`

`Bipolar Disorder
`
`important for the patient’s family physician
`and psychiatrist to develop an effective and
`collaborative relationship. Informed collabo-
`ration depends on an agreed method of com-
`munication in a frequency that meets the
`needs of each physician.** A Canadian model
`brings psychiatrists and counselorsinto family
`practice offices for shared care.*°
`At the onset of bipolar disorder, the family
`physician might seek psychiatric consultation
`for differential diagnosis and treatment rec-
`ommendations. Often,
`the psychiatrist
`assumes responsibility for initial manage-
`ment until
`the patient’s clinical pattern is
`determined. During follow-up, both physi-
`cians should monitorthe patient for signs of
`psychosis, mood swings, violence and self-
`harmful behaviors. As the patient’s illness sta-
`bilizes and management becomesroutine, the
`physicians can renegotiate, with each other
`and with thepatient, responsibility for ongo-
`ing care.
`Whenthe patient’s condition has become
`stable, the psychiatrist may not needto see the
`patientas often, although the frequency offol-
`low-up psychiatric visits depends on the
`course oftheillness, the patient’s adherence to
`treatment, medication requirements, the need
`for ongoing psychotherapy and patterns of
`care in a particular geographic area. It
`is
`important for the patient’s family physician
`and psychiatrist
`to coordinate medication
`prescriptions and follow-up laboratory tests
`such as determination of serum druglevels. In
`addition, counseling and family therapy are
`important components of management and
`may be rendered by the family physician, psy-
`chiatrist and/or psychologist.
`
`MEDICATION
`
`Recommendations for drug therapy in
`patients with bipolar disorder are summa-
`rized in Table 4.7
`Medication is the key to stabilizing bipolar
`disorder. Initial treatment of mania consists of
`lithium or valproic acid (Depakene). If the
`patientis psychotic, a neuroleptic medication
`
`Tricyclic antidepressants may induce rapid cycling of
`symptoms.
`
`is also given. Long-acting benzodiazepines
`may be used fortreating agitation. However,
`in patients with a substance-abuse history,
`benzodiazepines should be used with caution
`
`TABLE 4
`
`Recommendations for Drug Therapy in Patients
`with Bipolar Disorder
`
`Considerations for prescribing mood stabilizers
`Lithium: For classic, euphoric mania; for mixed manic episode; when a mood
`stabilizer alone is used to treat depression; when the moodstabilizer must be
`given in a single evening dose; in patients with liver disease, excessive alcohol
`use or cocaine use; and in patients older than 65 years
`Valproic acid (Depakene): For classic, euphoric mania; for mixed manic episode;
`for mania with rapid cycling; for long-term maintenance therapy in patients
`who do nottolerate lithium because of the “flat” feeling lithium causes; in
`patients with structural central nervous system disease, renal disease and
`cocaine use; and in patients older than 65 years
`Carbamazepine (Tegretol): For mixed manic episode; for mania with rapid cycling;
`in patients with structural central nervous system disease or renal disease
`An antipsychotic agent
`High- or medium-potency antipsychotic agents are used as adjunctive
`treatment for mania with psychosis or psychotic depression.
`A benzodiazepine
`Sleep and sedation in mania or hypomania; insomnia in depression
`
`The combination of a mood stabilizer, an antidepressant
`and an antipsychotic
`Psychotic depression
`
`The combination of a mood stabilizer and an antidepressant
`Nonpsychotic depression
`A moodstabilizer alone
`
`Milder depression in bipolar | disorder
`
`Bupropion (Wellbutrin)
`Bipolar depression
`Patient with high risk of manic switch or rapid cycling
`A selective serotonin reuptake inhibitor
`Bipolar depression
`
`Adapted with permission from Steering Committee. Treatment of bipolar disorder.
`The Expert Consensus Guideline Series. J Clin Psychiatry 1996;57(suppl 12A):3-88.
`aSeeee = aiS=s a
`
`
`
`SEPTEMBER 15, 2000 / VOLUME 62, NUMBER 6
`
`www.aafp.org/afp
`
`AMERICAN FAMILY PHYSICIAN
`
`1347
`
`5 of 11
`
`Alkermes, Ex. 1027
`
`5 of 11
`
`Alkermes, Ex. 1027
`
`

`

`
`TABLE 5
`Drug Interactions with Lithium
`
`Management
`Drug
`Effect on lithium level
`
`Thiazide diuretics
`
`Increased lithium level
`
`Loop diuretics
`
`Increased or decreased
`lithium level
`
`Potassium-sparing diuretics Decreased lithium level
`Nonsteroidal
`Increasedlithium level
`anti-inflammatory drugs
`
`Avoid this combination or reduce dosage;
`monitor lithium level
`
`Avoid this combination or alter either
`dosage as needed; monitor lithium level
`
`Monitor lithium level and adjust dosage
`
`Use lower dosage of lithium; consider
`aspirin or sulindac
`
`Increased lithium level;
`Angiotensin-converting
`enzyme inhibitors
`toxicity reported
`Calcium channel
`Increased or decreased
`lithium level
`blockers
`
`
`Use lower dosageoflithium; monitor
`lithium level closely
`
`Monitor lithium level closely
`
`Adapted with permission from DeVane CL, Nemeroff CB. 1998 Guide to psychotropic drug interactions.
`Primary Psychiatry 1998;5:36-75.
`
`
`
`
`because of the addictive potential of these
`agents.
`When the patient with bipolar disorder
`becomes depressed,a selective serotonin reup-
`take inhibitor (SSRI) or bupropion (Well-
`butrin) is recommended.”* Theuse oftricyclic
`
`antidepressants should be avoided because of
`the possibility of inducing rapid cycling of
`symptoms.
`Druginteractions are an important consid-
`eration when prescribing lithium (Table 5),?’
`valproic acid (Table 6)?’ and a selective sero-
`
`
`TABLE 6
`Drug Interactions with Valproic Acid (Depakene)
`
`
`Drug
`
`Phenobarbital
`
`Interaction
`
`Management
`
`Increased phenobarbital level
`
`Reduce dosage
`
`Magnesium- and aluminum-
`containing antacids
`
`Carbamazepine (Tegretol)
`
`Increased valproic acid level
`
`Monitor valproic acid level;
`reduce dosage
`
`Decreased valproic acid level; possible
`increased carbamazepine level
`
`Monitorvalproic acid level;
`adjust dosage
`
`Aspirin and naproxen
`(Naprosyn)
`
`Avoid salicylates or other drugs
`bound to plasma albumin
`Use with caution
`Increased sedation
`Clonazepam (Klonopin)
`
`
`Increased valproic acid level
`
`Adapted with permission from DeVvane CL, Nemeroff CB. 1998 Guide to psychotropic drug interactions.
`Primary Psychiatry 1998;5:36-75.
`
`
`
`
`1348
`
`AMERICAN FAMILY PHYSICIAN
`
`www.aafp.org/afp
`
`VOLUME 62, NUMBER 6 / SEPTEMBER 15, 2000
`
`6 of 11
`
`Alkermes, Ex. 1027
`
`6 of 11
`
`Alkermes, Ex. 1027
`
`

`

`Bipolar Disorder
`
`tonin reuptake inhibitor (Table 7).?” Informa-
`tion about starting and maintenance dosages
`for lithium, valproic acid and carbamazepine
`(Tegretol) is summarized in Table 8.?
`
`MONITORING ISSUES
`
`Treatment with mood stabilizers requires
`periodic laboratory tests to monitor the
`patient’s response to the drug (Table 9).?? In
`
`addition, preventive care includes surveillance
`for possible comorbidities. Screening for sub-
`stance abuse and other mental health prob-
`lems should be conducted routinely. If pro-
`dromal symptomsof depression or mania are
`noted, interventions may include more fre-
`quent office visits, crisis telephone calls and
`intensive outpatient programs.”? It is impor-
`tant that patients regulate their sleep. Insuffi-
`
`TABLE 7
`Drug Interactions with Selective Serotonin ReuptakeInhibitors
`
`Management
`Interaction
`Drug
`
`Alprazolam (Xanax)
`TCAs
`
`Increased alprazolam levels
`Increased TCA level
`
`Warfarin (Coumadin)
`
`Increased warfarin level with
`fluvoxamine (Luvox)
`
`MAOIs
`
`Serotonin syndrome
`
`Monitor; reduce dosage
`Monitor TCA level
`
`Monitor prothrombin time (INR);
`reduce fluvoxamine dosage
`Combination of MAOI and SSRI
`is contraindicated
`
`Clozapine (Clozaril)
`
`Increased clozapine level with fluvoxamine
`
`Monitor clozapine level
`
`L-Tryptophan
`
`Serotonin syndrome
`
`Phenytoin (Dilantin)
`
`Possible phenytoin toxicity
`
`Combination of t-tryptophan
`and SSRI is contraindicated
`
`Monitor phenytoin level
`
`Monitor carbamazpine level
`
`Carbamazepine
`(Tegretol)
`
`Tolbutamide
`
`Theophylline
`
`Increased carbamazepine level with
`fluvoxamine and fluoxetine (Prozac)
`
`Possible increased hypoglycemia
`
`Monitor blood glucoselevel
`
`Increased theophylline level with
`fluvoxamine
`
`Monitor theophylline level
`
`Cimetidine (Tagamet)
`
`Increased SSRI levels
`
`Monitor clinically
`
`Type Ic antiarrhythmics
`
`Beta-adrenergic blockers
`
`Codeine
`
`Increased antiarrhythmic level with
`fluoxetine, paroxetine (Paxil) and
`sertraline (Zoloft)
`Increased beta-blocker level and enhanced
`effects
`
`Inhibited metabolism from fluoxetine,
`paroxetine and sertraline
`
`Monitor antiarrhythmic drug
`levels
`
`Use lower beta-blocker dosage
`
`Use different SSRI
`
`Serotonin syndrome
`St. John’s wort
`Stop St. John’s wort before
`beginning SSRI therapy
`
`SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; INR = International Normalized
`Ratio; MAQI = monoamine oxidase inhibitor.
`
`Adapted with permission from DeVane CL, Nemeroff CB. 1998 Guide to psychotropic drug interactions.
`Primary Psychiatry 1998,5:36-75.
`
`SEPTEMBER 15, 2000 / VOLUME 62, NUMBER 6
`
`www.aafp.org/afp
`
`AMERICAN FAMILY PHYSICIAN
`
`1349
`
`7 of 11
`
`Alkermes, Ex. 1027
`
`7 of 11
`
`Alkermes, Ex. 1027
`
`

`

`cient and irregular hours of sleep often pre-
`cipitate mood disturbance.
`
`Family and PsychosocialIssues
`Significant issues for the patient and family
`membersinclude the stigmathatis frequently
`associated with mentalillness and the need for
`
`support and education. Because patients with
`bipolar disorder lose judgment early in the
`course ofthe illness and often engagein high-
`risk behavior, family members maybeinter-
`acting withthelegal system, the police and the
`health care system simultaneously. Guilt,
`anger, grief and ambivalence are frequentfeel-
`
`TABLE 8
`
`Starting and Maintenance DosagesofLithium, Valproic Acid and Carbamazepine and CommonSide Effects
`
`
`
`Cost
`initial dosing strategy* (generic)§ Maintenance dosaget
`Commonside effectst
`Lithium
`
`
`
`900 mg per day; increase
`by 300 to 600 mg every
`2 to 3 days as tolerated
`
`900 to 1,800 mg per day; 1,200 mg
`may be given as a single bedtime
`dose if tolerated; otherwise,
`prescribe twice-daily dosing
`Therapeutic blood level: 0.8 to 1.5
`mEq per L
`
`Thirst, polyuria, cognitive complaints,
`tremor,|| weight gain, sedation, diarrhea,
`nausea (watch for dehydration, which
`can lead to toxicity), hypothyroidism
`(monitor TSH; give levothyroxine
`[Synthroid] tf TSH is elevated)
`
`One 300-mg
`capsule: $0.19
`(0.06 to 0.10)
`
`Valproic acid (Depakene)
`20 mg per kg per day for
`mania; adjust dosage in
`3 to 5 days
`An alternative is 500 to 750
`
`mg daily; increase by 30
`to 50 percent every 2 to 3
`days as tolerated
`
`1,000 to 3,000 mg per day. Lower
`dosages may be used in hypomania.
`Sometimes it is appropriate to give
`as a single bedtime dase; otherwise,
`prescribe twice-daily dosing
`Therapeutic blood level: 50 to
`125 ug per mL
`
`Tremor,|| sedation, diarrhea, nausea (use
`divalproex [Depakote]; give histamine
`H,-receptor blocker such as ranitidine
`[Zantac], 150 mg daily); weight gain,
`hair lass, mild elevation on liver
`function tests
`
`One 250-mg
`capsule:
`$1.24
`
`Carbamazepine (Tegretol)
`200 to 400 per day; increase
`by 200 mg daily every 2
`to 4 days
`
`400 to 1,200 mg daily; in an
`occasional patient, it is appropriate
`to give a single bedtime dose;
`otherwise, prescribe twice-daily
`dosing
`Therapeutic blood level: 4 to 12 ug
`per mL; not well established
`
`Headache, nystagmus, ataxia, sedation,
`rash, leukopenia (do not combine with
`clozapine [Clorazil]}, mild elevation on
`liver function tests, Carbamazepine is
`associated with frequent drug-drug
`interactions related to induction of
`cytochrome P450 liver enzymes,
`resulting in lower drug levels of many
`other medications.
`
`
`One 200-mg
`tablet: $0.44
`(0.29 to 0.33)
`
`TSH = thyroid-stimulating hormone.
`
`*—Wheninitiating therapy, consider lower dosages in patients with hypomania and in medically ill or elderly patients.
`t—Consolidate doses to twice daily or once daily at bedtime if tolerated and efficacious.
`¢—Manyof the side effects are dose related. Tolerance can be enhancedby tailoring the dasage to each patient’s tolerance and response,
`§—Estimated cost to the pharmacist for one tablet or capsule based on average wholesale prices rounded to the nearest dollar in Red
`book. Montvale, N.1.: Medical Economics Data, 1999. Cost to the patient will be higher, depending on prescriptionfilling fee.
`|Tremor may be relieved with a beta-adrenergic blocker such as atenolol (Tenormin), in a dosage af 50 mg aaily.
`
`Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus Guideline Series. J Clin Psychia-
`try 1996;57(supp! 12A):3-88.
`
`1350
`
`AMERICAN FAMILY PHYSICIAN
`
`www.aafp.org/afp
`
`VOLUME 62, NUMBER 6 / SEPTEMBER 15, 2000
`
`8 of 11
`
`Alkermes, Ex. 1027
`
`8 of 11
`
`Alkermes, Ex. 1027
`
`

`

`Bipolar Disorder
`
`Easy access to firearms can supply a ready meansofsuicide
`or accident in patients with bipolar disorder.
`
`ings among family membersas they cope with
`the difficulties.
`Family members must be educated about
`possible relapses, what to look for and how to
`handle different situations. The recklessness
`that accompanies mania can have devastating
`including informational pamphlets, videos
`consequences—including sexually transmit-
`ted diseases, financial ruin, traumatic injuries
`and involvementin support and patient advo-
`and accidents. Risk-taking causes significant
`cacy groups.
`distress to patients and families, and such
`Patients who are manic or depressed may
`behavioris a problem for which family physi-
`attempt suicide or homicide. The risk is
`increased in patients who are psychotic and
`cians, psychiatrists and mental health profes-
`sionals can intervene with appropriate med-
`have severe depressive symptoms concurrent
`with mania.”® The lifetime suicide risk is 15
`ical, preventive, educational and_social
`strategies (Table 10).** Initial
`intervention
`percent
`in patients with bipolar disorder;
`includes education for the patient and family,
`patients at highest risk are young men in an
`
`SSeSSE
`
`TABLE 9
`
`Recommended Laboratory Tests for Monitoring Response
`to Lithium, Valproic Acid and Carbamazepine
`
`Lithium
`Valproic acid (Depakene) Carbamazepine (Tegretol)
`
`
`
`First two months of therapy
`Serum level every 1
`to 2 weeks* +
`
`Long-term therapy
`Serum level every 3 to
`6 months*t
`Thyraid function tests yearly
`(total T,, T, uptake and TSH)+
`
`Renal function every 6 to 12
`months (serum urea nitrogen,
`creatinine and electrolytes);
`24-hour urine for volume and
`GFR only if specifically indicated,
`not routinely
`
`Serum level every 1 to 2
`weeks*
`CBC and liver function
`tests monthly
`
`Serum level every 1 to 2
`weeks*
`CBC and liver function
`tests monthly
`
`Serum level every 3 to 6
`months* f
`CBC and liver function
`tests every 6 to 12 months
`
`Serum level every 3 to 6
`months*
`CBC and liver function
`tests every 6 months
`
`
`
`CBC = complete blood count; T, = thyroxine; TSH = thyrojd-stimulating hormone; GFR = glomerularfiltration
`rate.
`
`*—_Serum levels of moodstabilizers should be obtained whenever the dosageorclinical situation changes.
`t—Tests are strongly recommended by the committee that formulated the guidelines for treatment of bipo-
`lar disorder.
`
`Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expert Consensus
`Guideline Series. J Clin Psychiatry 1996;57(supp! 12A).3-88.
`
`SS SS SS SSS SSSaeeee
`
`SEPTEMBER 15, 2000 / VOLUME 62, NUMBER 6
`
`www.aafp.org/afp
`
`AMERICAN FAMILY PHYSICIAN
`
`1351
`
`9 of 11
`
`Alkermes, Ex. 1027
`
`9 of 11
`
`Alkermes, Ex. 1027
`
`

`

`TABLE 10
`
`Psychosocial Issues to Address in the Acute and Maintenance Phases
`of Bipolar Disorder
`
`Acute phase
`
`Maintenance phase
`
`Monitor suicidality, mood, substance use, sleep
`patterns and medication compliance.
`
`Inquire aboutsuicidality, mood, medication compliance,
`life events, substance use, sleep and activity.
`
`Educate patient and family members about
`features and biologic nature of theillness and
`the importance of compliance with therapy.
`
`Encourage telephone contact and optimism
`regarding recovery. Setlimits on impulsive
`behavior in patients with mania. Consider
`interpersonal or cognitive therapy for patients
`with depression. Hald family meetings to
`discuss issues.
`
`Educate patient and family members about use of
`medication, warning signs of relapse, management
`of stress, sleep hygiene, eating and exercising
`regularly, limited caffeine and alcohol intake and
`management of work andleisure activities.
`
`Long-range issues may include marital problems,
`employment and financial problems, peer
`relationships and modification of personality traits.
`
`Adapted with permission from Steering Committee. Treatment of bipolar disorder. The Expe