ackground:

Manic-depressive illness (MDI) is one of the most common,

evere, and persistent mental illnesses.

is characterized by periods of

eep,

rolonged,

rofound depression

hat alternate with periods of excessively elevated

nd/or irritable mood known as MANIA

he symptoms of mania include:

ecreased need for sleep,

ressured speech,

ncreased libido,

eckless behavior without regard for consequences,

randiosity,

nd severe thought disturbances,

Which may or may not include psychosis.

athophysiology: The etiology and pathophysiology of bipolar disorder have not been determined, and no objective biological markers e
efinitively with the disease state.

owever, twin, family, and adoption studies all indicate strongly that bipolar disorder has a genetic component.

n fact, first-degree relatives of a person with bipolar disorder are approximately 7 times more likely to develop bipolar disorder than the re
enetic studies of patients with bipolar disorder are ongoing and are expected to be facilitated by recent advances in information and tec
art, by the Human Genome Project.

ace: No racial predilection exists.

owever, a point of historical interest is that clinicians often tend to consider populations of African Americans and Hispanics as more like
ith schizophrenia than with affective disorders and MDI.

ex: BPI occurs equally in both sexes;

 owever, rapid-cycling bipolar disorder (4 or more episodes a year) is more common in women than in men.

ncidence of BPII is higher in females than in males.

ge: The age of onset of MDI varies greatly.

he age range for both types of bipolar disorders is from childhood to 50 years,

With a mean age of approximately 21 years.

Most cases commence when individuals are aged 15-19 years.

he second most frequent age of onset is 20-24 years.

hey may have a family history of bipolar disorder.

owever, for most patients, the onset of mania after age 50 years should lead to an investigation for medical or neurological disorders su
sease.

istory:

he diagnosis of BPI disorder requires the presence of a

Manic episode of at least 1 week's duration that leads to hospitalisation

r other significant impairment in occupational or social functioning.

he episode of mania cannot be caused by another medical illness or by substance abuse. These criteria are based on the specifications
tatistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR).

• Manic episodes are characterized by the following symptoms:

o At least 1 week of profound mood disturbance is present, characterized by

o elation,
o irritability,
o or expansiveness

o Three or more of the following symptoms are present:

 Grandiosity
 Diminished need for sleep
 Excessive talking or pressured speech
 Racing thoughts or flight of ideas
 Clear evidence of distractibility
 Increased level of goal-focused activity at home, at work, or sexually
 Excessive pleasurable activities, often with painful consequences
 o The mood disturbance is sufficient to cause impairment at work or danger to the patient or others.

o The mood is not the result of substance abuse or a medical condition.

• Major depressive episodes are characterized by the following:

o For the same 2 weeks, the person experiences 5 or more of the following symptoms, with at least 1 of them being either
characterized by a loss of pleasure or interest:
 Depressed mood
 Markedly diminished pleasure or interest in nearly all activities
 Significant weight loss or gain or significant loss or increase in appetite
 Hypersomnia or insomnia
 Psychomotor retardation or agitation
 Loss of energy or fatigue
 Decreased concentration ability or marked indecisiveness
 Preoccupation with death or suicide; patient has either a plan or has attempted suicide

o The symptoms cause significant impairment and distress.

o The mood is not the result of substance abuse or a medical condition.

• Appearance

o Depressed episode:
o Persons experiencing a depressed episode
o demonstrate poor to no eye contact.
o Their clothes are unkempt,
o unclean,
o holed,
o unironed, and
o ill fitting.
o If significant weight loss has occurred, the garments may fit loosely.

The personal hygiene of individuals experiencing a depressed episode reflects their:

low mood,

as evidenced by;

poor grooming,

lack of shaving, and lack of washing.

In women, fingernails may show different layers of polish

or one layer partially removed.

They may not have paid attention to their hair.

Men may exhibit dirty fingernails and hands.

 When these individuals move, their depressed affect is demonstrated.

They move slowly and very little.

They show psychomotor retardation.

They may talk in low tones or in a depressed or monotone voice.

o
o Manic episode:
o In many ways, the behavior of a patient in the manic phase reflects behavior opposite of a person in the depressed phase
o Patients experiencing the manic phase are hyperactive
o and might be hypervigilant.
o They are restless,
o energized, and active.
o They talk and act fast.

Their attire reflects the mania.

Their clothes might have been put on in haste

and are disorganized.

Alternately, their garments often are too bright, colorful, or garish.

They stand out in a crowd because their dress frequently attracts attention.

• Affect/mood

o Depressed episode:
o Sadness dominates the affect of individuals experiencing a depressed episode.
o They feel sad,
o depressed,
o lost,
o vacant,
o and isolated.
o The “2 Hs” command their mood, hopeless and helpless.
o When in the presence of such patients, one comes away feeling sad and down.
o
o Manic episode:
o The mood is inappropriately joyous,
o elated,
o and jubilant.
o They are euphoric.
o They also may demonstrate annoyance and irritability,
o especially if the mania has been present for a significant length of time.
o

• Thought content

o Depressed episode:
o Patients experiencing a depression have thoughts that reflect their sadness.
o They are preoccupied with negative ideas and nihilistic concerns,
o and they metaphorically see “the glass as half empty."
 o They likely are to focus on death and morbid subjects.
o Many think about suicide.

o
o Manic episode:
o During the manic phase:
o patients have very expansive and optimistic thinking.
o They may be excessively self-confident and/or grandiose.
o They often have a very rapid production of ideas and thoughts.
o They perceive their minds as being very active and see themselves as being highly engaging and creative.
o They are highly distractible and quickly shift from one subject to another.
o .

• Perceptions

o Depression episode:
o Two forms of a major depression are described.
o One has psychotic features and the other does not.
o With psychosis, the patient experiences:
o delusions and
o hallucinations that are either consistent or inconsistent with the mood.
o In the former,
o the patient's delusions of having sinned are accompanied by:
o guilt and remorse
o or the patient feels he or she is utterly worthless
o and should live in total deprivation and degradation.
o Hence, the delusional content remains consistent with the depressed affect.

In contrast, some patients experience delusions that are inconsistent with the depression.

For example, the individual feels that:

he is the Messiah in the presence of his very depressed affect.

o
o Manic episode:
o Approximately three fourths of patients in the manic phase have delusions.
o As in major depression, the delusional content is either consistent or inconsistent with the mania.
o Manic delusions reflect perceptions of power,
o prestige,
o position,
o self-worth,
o and glory.
o

• Suicide/self-destruction

o Depressed episode:
o Depressed patients have a very high rate of suicide.
o They are the individuals who attempt and succeed at killing themselves.
o Query patients to determine if they have any thoughts of hurting themselves (suicidal ideation)
o and any plans to do so.
o The more specific the plan,
o the higher the danger.
o As patients emerge from a period of depression,
 o their suicide risk may increase.
o This may be because, as the illness remits,
o executive functions are improved such that the person is again capable of making and carrying out a plan.
o
o Manic episode:
o Incidence of suicide is low.

• Homicide/violence/aggression

o Depressed episode:
o Generally,
o suicide remains the paramount issue.
o However, certain persons in the depths of a depression not only see the world as:
o hopeless
o and helpless for themselves but also for others.
o Frequently, that perspective can create and lead to a homicide followed by a suicide.
o One example of this occurred when a 42-year-old mother of 2
o was experiencing a significant depression as part of her bipolar disorder.
o She believed the earth was doomed and was a terrible place to dwell.
o Furthermore, she thought that if she died,
o her children would be left in a wretched place.
o Because of this view, she planned to kill her 2 children and then herself.
o Fortunately, her family recognized the state of affairs, which led to an emergency intervention and her hospitalization.

o
o Manic episode:
o Persons in mania can be openly combative and aggressive.
o They have no patience or tolerance for others.
o They can be highly demanding,
o violently assertive,
o and highly irritable.
o
o The homicidal element particularly emerges if these individuals have a delusional content to their mania.
o They are acting out of the grandiose belief that others must obey their commands,
o wishes, and directives.
o If their delusions become persecutory in nature,
o they may defend themselves against others in a homicidal fashion.
o

• Judgment/insight

o Depressed episode:
o Depression clouds and dims these individuals' judgment and colors their insights.
o They fail to make important actions because they are so down and preoccupied with their own plight.
o They see no tomorrow; therefore, planning for it is very difficult.
o Frequently, persons in the middle of a depression have done things such as forgetting to pay their income taxes.
o
o At that time, they have little insight into their behavior.
o Often, others have to persuade them to seek therapy because of their lack of insight.
o

o Manic episode:
o The hallmark of this phase is seriously impaired judgment.
o They make terrible decisions in terms of their work and family.
o They may invest the family fortune in very questionable programs.
 o They may become professionally over-involved in work activities or with coworkers.
o They start a series of dramatic very unsound fiscal or professional ventures.
o They do not listen to any feedback,
o suggestions, or advice from friends, family, or colleagues.
o They have no insight into the extreme nature of their demands, plans, and behavior.
o Often, commitment proves the only way to contain them.
o

• Sensorium:
• Impairments in orientation and memory are seldom observed in patients with bipolar disorder unless they are very psychotic.
• They know the time and their location,
• and they recognize people.
• They can remember immediate, recent, and distant events.
• In some cases of hypomanic and even manic episodes,
• their ability to recall information can be extremely vivid and expanded.
• In extremes of depression and mania, they may experience difficulty in concentrating and focusing.

auses: Bipolar disorder has a number of contributing factors, including:

enetic,

ochemical,

sychodynamic,

nd environmental elements.

• Genetics

o Bipolar disorder, especially BPI, has a major genetic component.

o The evidence indicating a genetic role in bipolar disorder takes several forms.

o First-degree relatives of people with BPI are approximately 7 times more likely to develop BPI than the general population
o Remarkably, offspring of a parent with bipolar disorder have a 50% chance of having another major psychiatric disorder.

o
o Twin studies:
o demonstrate a concordance of 33-90% for BPI in identical twins.

o Adoption studies:
o prove that a common environment is not the only factor that makes bipolar disorder occur in families.
o Children whose biologic parents have either BPI disorder or a major depressive disorder remain at increased risk of deve
disorder, even if they are reared in a home with adopted parents who are not affected.

o Numerous genetic studies of BPI disorder suggest multiple different genetic loci,
o but, as yet, no genes have been definitively identified.
o This is, in part, because many genes contribute small effects to the disorder in different individuals
o and, partly, because no objective means of identifying a particular genetic subtype is available.
o However, studies are ongoing, and technological and statistical advances may lead to a breakthrough in the next decade
o A very interesting new finding in psychiatric genetics heralds the future revision of DSM-IV-TR according to an etiological
basis.
o Using probands from the Maudsley Twin Register in London, Cardno and colleagues showed that schizophrenic,
 o schizoaffective,
o and manic syndromes share genetic risk factors
o and that the genetic liability for schizoaffective disorder was entirely shared in common with the other two syndromes.
o This finding suggests an independent genetic liability for psychosis shared by both mood and schizophrenia spectrum dis
previously speculated.
o A recent study by Tsuang et al further indicates the genetic contribution to MDI with psychotic features. Their findings sho
schizophrenia and bipolar disorder (Tsuang, 2004).

• Biochemical causes

o Multiple biochemical pathways likely contribute to bipolar disorder, which is why detecting one particular abnormality is di

o A number of neurotransmitters have been linked to this disorder, largely based on patients' responses to psychoactive ag

o For instance, the blood pressure drug reserpine,

o which dampens catecholaminergic transmission,
o was noted incidentally to cause depression.
o This led to the catecholamine hypothesis,
o which holds that an increase in epinephrine and norepinephrine causes mania
o and a decrease in epinephrine and norepinephrine causes depression.

o Drugs like cocaine, which also act on this neurotransmitter system, exacerbate mania.

o Other agents that exacerbate mania include L-dopa,

o which implicates dopamine and serotonin-reuptake inhibitors, which, in turn, implicate serotonin.

o Calcium channel blockers have been used to treat mania,

o which also may result from a disruption of calcium regulation in neurons.
o The proposed disruption of calcium regulation may be caused by a variety of neurologic insults such as excessive glutam
ischemia.
o Interestingly, valproate specifically up-regulates expression of a calcium chaperone protein, GRP 78, which may be one o
of cellular protection.

o Hormonal imbalances and disruptions of the hypothalamic-pituitary-adrenal axis involved in homeostasis and the stress r
contribute to the clinical picture of bipolar disorder.

• Psychodynamic

o Many practitioners see the dynamics of MDI as being linked through one common pathway.

o They see the depression as the manifestation of the losses,

o ie, the loss of self-esteem and the sense of worthlessness.
o Therefore, that mania serves as a defense against the feelings of depression. (Melanie Klein was one of the major propo
formulation.)

• Environmental

o In some instances, the cycle either may be directly linked to external stresses
o or the external pressures may serve to exacerbate some underlying genetic
o or biochemical predisposition.
o Pregnancy is a particular stress for women with an MDI history and increases the possibility of postpartum psychosis (Ch

o Because of the nature of their work,

o certain individuals have periods of high demands followed by periods of few requirements.
 o For example, one person was a landscaper and gardener. In the spring, summer, and fall, he was very busy.
o During the winter, he was relatively inactive except for plowing snow.
o Thus, he appeared manic for a good part of the year, and then he would crash and hibernate for the cold months.

ab Studies:

• Standard laboratory studies:

• A number of reasons exist to obtain the following laboratory studies.
• First, the practitioner needs to perform the tests to determine the diagnosis.
• Because bipolar disorder encompasses both depression and mania
• nd because a significant number of medical causes for each state exists,
• an extensive range of tests is indicated.
• The basic principle remains, "do not miss a treatable medical cause for the mental status."
• Second, the physician employs a number of medications that require certain body systems to be working properly;
• for example, lithium requires an intact genitourinary (GU) system
• and can affect certain other systems,
• and certain anticonvulsants can suppress bone marrow.
• Third, because bipolar illness is a lifelong disorder, performing certain baseline studies is important to establish any long-term eff

o CBC count with differential: This test is used to rule out anemia as a cause of depression. Treatment, especially with cert
hence, the need to check the red and white blood counts for signs of bone marrow suppression. Lithium may cause a rev

o Sedimentation rate: This test is used to look for any underlying disease process such a lupus or an infection. An elevated
process.

o Glucose-level fasting: This test is used to rule out diabetes. Atypical antipsychotics have been associated with weight gai
patients with diabetes.

o Electrolytes: This test is used to diagnose electrolyte problems, especially with sodium, that are related to depression. Hy
depression. Treatment with lithium can lead to renal problems and electrolyte problems. Low sodium levels can lead to h
screening candidates for lithium therapy as well as those on lithium therapy, checking electrolytes is indicated.

o Serum calcium: This test is used to diagnose hypercalcium and hypocalcium levels associated with mental status change
as evidenced by an elevated calcium blood level, produces depression. Certain antidepressants, such as nortriptyline, af
important.

o Serum proteins: Low serum proteins found in patients who are depressed may be a result of not eating. Low serum prote
because they have less protein to which to bind.

o Thyroid studies: Perform thyroid tests to rule out hyperthyroidism (mania) and hypothyroidism (depression). Treatment w

o Substance and alcohol screen: Alcohol abuse and abuse of a wide variety of drugs can present as either mania or depre
 cocaine abuse can present as a manialike disorder, and barbiturate abuse can present as a depressionlike disorder. A nu
have a drug or alcohol addiction; therefore, they have dual diagnoses. Performing a substance screen helps make this du
monitoring for these substances is important.

o Urine copper level: This test is used to rule out Wilson disease, which produces mental changes. It is a rare disease that

o Antinuclear antibody: This test is used to rule out lupus.

• Infectious screening tests:

• A number of infections, especially chronic infections, can produce a presentation of depression in the patient.
• Any of the encephalitides can dramatically manifest as changes in mental status.

o HIV test: AIDS causes changes in mental status, including dementia and depression.

o VDRL test: Syphilis, especially in its later stage, alters mental status.

• Serum creatinine and BUN:

• Kidney failure can present as depression.
• Treatment with lithium can affect urinary clearances, and serum creatinine and BUN can increase.
• Therefore, carefully and regularly monitor these levels.

• ECG: Many of the antidepressants, especially the tricyclics and some of the antipsychotics,
• can affect the heart and cause conduction problems.
• Lithium also can lead to changes such as reversible flattening or inversion of T waves.
• A pretreatment ECG is important.

maging Studies:

• The total value of performing an MRI in a patient with bipolar disorder remains unclear;
• however, a couple of reasons do exist for performing an imaging study.

o Because MDI is a lifelong disease, a strong battery of studies rules out any other medical etiology and establishes a base

o Some investigators report that patients with mania have hyperintensity in their temporal lobes.

ther Tests:

• The reasons for ordering an electroencephalogram (EEG) in patients with bipolar illness are as follows:

o EEG provides a baseline and helps rule out any neurologic problems.
o Use this test to rule out a seizure disorder and brain tumor.

o If electroconvulsive therapy (ECT) is contemplated, an EEG is required.

o Some studies have shown that EEG abnormalities have been indicative of anticonvulsant effectiveness.
o Specifically, an abnormal EEG predicts the response to divalproex.

o Some patients may have seizures when on medications, especially antidepressants.

o Also, lithium can cause diffuse slowing.

Medical Care: The treatment of bipolar disorder is directly related to the phase of the episode,
g, depression or mania,

nd the severity of that phase.

or example, a person who is extremely depressed and exhibits suicidal behavior requires inpatient treatment.

n contrast, an individual with a moderate depression who still can work would be treated as an outpatient.

• Inpatient hospital treatment:

• The indications for hospitalization in a person with bipolar disorder include the following:

o Danger to self: A patient, especially one in a depressive episode, may present with a significant risk for suicide. Serious s
constitute clear evidence of the need for constant observation and preventive protection; however, in other situations, the
of the disease. For example, a person who is depressed enough to not eat might be at risk of death. Alternately, a person
food, may be in a state of serious exhaustion.
o Danger to others: Patients with bipolar disorder can become a threat to others. For example, a patient experiencing a sev
that she planned to kill her children to spare them from the world's misery. In the other extreme, a delusional patient havi
him; he searched for a rifle in order to defend himself and to get them before they got him.
o Total inability to function: Occasionally, depression is so profound that the person cannot function at all.
o Leaving such a person alone would be dangerous and not therapeutic.
o Totally out of control: This is true especially during a manic episode. In this situation, a person's behavior is so beyond lim
o they are destroying their career and can be harmful to those around them.
o Medical conditions that warrant medication monitoring:
o For example, patients with certain cardiac conditions should be in a medical environment where the effects of the psycho
closely.

• Partial hospitalization or a day-treatment program

o In general, these patients have severe symptoms but have a level of control and a stable living environment.
o For example, a patient with severe depression who has thoughts of suicide but no plans to act upon them
o and who has a high degree of motivation can get well when given a great deal of interpersonal support,
o especially during the day,
o and with the help of a very involved and supportive family.
o The family needs to be home every night and should be very concerned with the patient's care.
o Partial hospitalization also offers a bridge to return to work.
o Returning directly to work often is difficult for patients with severe symptoms,
o and partial hospitalization provides support and interpersonal relationships.
• Outpatient treatment

o Outpatient treatment has 4 major goals.

o First, look at areas of stress and find ways to handle them. The stresses can stem from family or work, but if they accumu
o they propel the person into mania or depression. This is a form of psychotherapy.
o Second, monitor and support the medication.
o Medications make an incredible difference.
o The key is to get the benefits and avoid adverse effects.
o Patients are ambivalent about their medications.
o They recognize that the drugs help and prevent hospitalizations,
o yet they also resent that they need them.
o The job is to address their feelings and allow them to continue with the medications.
o Third, develop and maintain the therapeutic alliance.
o This is one of the many reasons for the practitioner to deal with the patient's ambivalence about the medications.
o Over time, the strength of the alliance helps keep the patient's symptoms at a minimum and helps the patient remain in th

o The fourth aspect involves education.

 o The clinician must help educate both the patient and the family about bipolar illness.
o They need to be aware of the dangers of substance abuse,
o the situations that would lead to relapse,
o and the essential role of medications.
o Support groups for patients and families are of tremendous importance.

ctivity: Patients in the depressed phase are encouraged to exercise. Propose a regular exercise schedule for all patients, especially tho
egular schedule are keys to surviving this illness. However, increases in exercise level, with increased perspiration, can lead to increase

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MEDICATION Section 7 of 10

Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

ppropriate medication depends on the stage of the bipolar disorder the patient is experiencing. Thus, a number of drugs are indicated fo
ntipsychotics and benzodiazepines (eg, lorazepam, clonazepam). The choice of agent depends on the presence of symptoms such as p
eep disturbance. Atypical antipsychotics are being used increasingly for treatment of both acute mania and mood stabilization. The broa
n acute depressive episode (ie, major depression). Finally, another set of medications is chosen for the maintenance and preventive pha

linical experiences have shown that, if treated with mood-stabilizing drugs, patients with bipolar disorder have fewer episodes of mania
abilize the patient's mood, as the name implies. They also can dampen extremes of mania or depression.

rug Category: Mood stabilizers -- Lithium is the drug commonly used for prophylaxis and treatment of manic episodes. A recent study su
ole (Bauer, 2003).

rug Name Lithium carbonate (Duralith, Eskalith, Lithobid) -- Considered a first-line agent for long-term
 prophylaxis in bipolar illness, especially for classic bipolar disorder with euphoric mania. Also c
be used to treat acute mania, although cannot be titrated up to an effective level as quickly as
valproic acid. Evidence suggests that lithium, unlike any other mood stabilizer, may have a
specific antisuicide effect. Monitoring blood levels is critical with this medication.
Maintenance, preventive use: 400-1200 mg (0.6-1 mmol/L) PO qd
dult Dose
Acute manic episode: 600-2400 mg PO (0.8-1.2 mmol/L) qd
<6 years: Not established
ediatric Dose 6-12 years: 15-60 mg/kg/d PO divided tid/qid; not to exceed adult dose
>12 years: Administer as in adults
Documented hypersensitivity; renal disease or damage (renal function and clearance are critica
ontraindications in maintaining proper levels); history or evidence of brain damage; cardiovascular disease;
generalized severe debilitation
Increases toxicity of thiazide diuretics, haloperidol, phenothiazines, neuromuscular blockers,
nteractions
carbamazepine, fluoxetine, and ACE inhibitors
regnancy D - Unsafe in pregnancy
Patient should have adequate renal function as evidenced by elevated creatinine levels or BUN
levels, and they should drink plenty of fluids to prevent dehydration; excessive sodium loss can
produce lithium toxicity (avoid excessive sweating); use lower doses in elderly individuals; do n
recautions perform ECT when being administered; avoid rapid increases in dosing
Anything causing hyponatremia increases levels and could cause toxicity; toxicity is closely
related to serum levels and can occur at therapeutic doses; serum lithium determinations are
required to monitor therapy

rug Category: Anticonvulsants -- Have been effective in preventing mood swings associated with bipolar disorder, especially in patients
mood stabilizers, such as lithium and lamotrigine, are preferred because antidepressants may propel a patient into a manic episode or ex
abapentin, although not a mood stabilizer, also may have antidepressant and anxiolytic properties. The most widely used anticonvulsan
nd lamotrigine. More recently, topiramate and tiagabine also are being tried.

Carbamazepine (Tegretol) -- Effective in patients who have not responded to lithium therapy. A
can act to inhibit seizures induced through the kindling effect, which is thought to occur by way
rug Name
repeated limbic stimulation. Has been effective in treating patients who have rapid-cycling bipol
disorder or those who have not been responsive to lithium therapy.
Initial: 200 mg PO qd in divided doses with increments of 100 mg 2 times/wk; if adverse effects
occur, decrease dose by 200 mg
Dose range: 300-1600 mg PO qd
dult Dose
Serum level range: 17-50 mmol/L (4-12 mcg/mL)
Manic episode: 200-1800 mg PO qd
Plasma level: 4-12 mcg/mL
<6 years: Not established
6-12 years: 100 mg PO bid or 10 mg/kg/d divided bid initially, then increase to 100 mg/d every
ediatric Dose
Maintenance: 20-30 mg/kg/d PO divided bid/qid; not to exceed 1000 mg/d
>12 years: Administer as in adults to achieve 4-12 mcg/mL plasma level
Documented hypersensitivity; administration of MAOIs within last 14 d; history of liver disease,
ontraindications
cardiovascular disease, and blood dyscrasias
Halothane coadministration may cause hepatocellular damage; grapefruit juice, influenza vacci
isoniazid, cimetidine, erythromycin, and phenelzine increase plasma levels; phenytoin,
alprazolam, clonazepam, primidone, and phenobarbital decrease both CBZ level and levels of
interacting agents; fluoxetine increases level; decreases levels of imipramine, phenothiazines,
haloperidol, theophylline, thyroid hormones, ritonavir, saquinavir, contraceptives, risperidone,
nteractions
thiothixene, cyclosporine, corticosteroids, doxycycline, trazodone, doxepin, and amitriptyline;
increases plasma levels of diltiazem and verapamil; can reduce its own level by "autoinduction;
coadministration with lithium or loxapine increases toxicity of both CBZ and the interacting agen
coadministration with clozapine further increases bone marrow toxicity and resulting
agranulocytosis
regnancy D - Unsafe in pregnancy
 There is a very small, but significant, risk of causing agranulocytosis or aplastic anemia.
During drug initiation, avoid using hazardous equipment or driving; other depressants and alcoh
recautions may lead to increased dizziness and sleepiness; keep in a dry place; drinking grapefruit juice
while taking CBZ elevates blood levels; report any indications of blood dyscrasias (eg, easy
bruising, sore throats, fever, rash)
Valproate sodium, valproic acid (Depakene, Depakote) -- Has proven effectiveness in treating a
preventing mania. Classified as a mood stabilizer and can be used alone or in combination with
rug Name lithium. Useful in treating patients with rapid-cycling bipolar disorders and has been used to trea
aggressive or behavioral disorders. A combination of valproic acid and valproate has been
effective in treating persons in manic phase, with a success rate of 49%.
250 mg PO tid, initially in increments until a serum level of 350-700 mmol/L (50-100 mcg/mL) h
been achieved
Maintenance: 750-3000 mg PO qd in divided doses
dult Dose
Manic episode: Loading dose of 20 mg/kg/d PO
Stat dose: 20 mg/kg PO, with next dose in 12 h; then 10 mg/kg bid
Maintenance: 500-3500 mg PO qd to achieve plasma level of 50-125 mcg/mL
10-15 mg/kg/d PO initially in 1-3 divided doses; increase by 5-10 mg/kg/d PO every wk until
ediatric Dose therapeutic plasma level achieved
Maintenance: 30-60 mg/kg/d PO divided bid/tid
ontraindications Documented hypersensitivity, hepatic disease/dysfunction
Coadministration with cimetidine, salicylates, felbamate, and erythromycin may increase toxicity
rifampin may significantly reduce valproate levels; in pediatric patients, protein binding and
metabolism of valproate decrease when taken concomitantly with salicylates; coadministration
with carbamazepine may result in variable changes of carbamazepine concentrations, with
nteractions
possible loss of seizure control; valproate may increase diazepam and ethosuximide toxicity
(monitor closely); valproate may increase phenobarbital and phenytoin levels, while either one
may decrease valproate levels; valproate may displace warfarin from protein binding sites
(monitor coagulation tests); may increase zidovudine levels in patient seropositive for HIV
regnancy D - Unsafe in pregnancy
Monitor for hepatic toxicity (obtain liver function tests prior to initiating therapy and thereafter);
serum ammonia levels may increase independently of other liver functions and may cause alter
mental status; check platelet count and bleeding times prior to therapy and during treatment;
recautions
valproic acid inhibits cytochrome P-450 metabolism system (pay attention to any drugs that use
this system); monitor for symptoms of pancreatitis and pancreatic enzymes because hemorrhag
pancreatitis has been reported
Gabapentin (Neurontin) -- Not a mood stabilizer and cannot be used to treat mania. May have
rug Name useful antidepressant and anxiolytic effects in depressed or irritable patients. Has few drug-to-
drug interactions.
dult Dose 900-1800 mg PO in divided doses, not to exceed 3600 mg/d
ediatric Dose Not established
ontraindications Documented hypersensitivity
Antacids may significantly reduce bioavailability (administer at least 2 h following antacids); ma
nteractions increase norethindrone levels significantly; can potentiate sedating effects of other CNS
depressant drugs
regnancy C - Safety for use during pregnancy has not been established.
recautions Caution in severe renal disease
Lamotrigine (Lamictal) -- Anticonvulsant that appears to be effective in the treatment of the
rug Name
depressed-phase in bipolar disorders.
12.5-37.5 mg/d PO, initially, gradually titrated in 25-mg increments not more often than weekly;
dult Dose
effective dose usually 100-400 mg/d qd or divided bid
ediatric Dose 2-15 mg/kg/d PO divided bid initially
ontraindications Documented hypersensitivity; lactation; renal impairment; hepatic and cardiac problems
 Acetaminophen increases renal clearance and decreases effects; similarly, phenobarbital and
nteractions phenytoin increase metabolism, causing a decrease in levels; concurrent administration with
valproic acid increases lamotrigine levels
regnancy C - Safety for use during pregnancy has not been established.
Can cause adverse CNS effects, including dizziness, sedation, ataxia, nystagmus, and diplopia
dermatological problems include hypersensitivity rash, Stevens-Johnson syndrome, and
recautions angioedema; renal involvement can produce hematuria; caution in impaired renal or hepatic
function; fatal hypersensitivity reactions to lamotrigine are more likely to occur with rapid dose
increments (caution when coadministered with valproate)

rug Category: Antipsychotic agents -- Atypical antipsychotics are being used increasingly for treatment of both acute mania and mood s

Ziprasidone (Geodon) -- Indicated to treat acute bipolar mania, including manic and mixed
episodes. Antagonizes dopamine D2, D3, 5-HT2A, 5-HT2C, 5-HT1A, 5-HT1D, and alpha1adrenergic.
rug Name Has moderate antagonistic effect for histamine H1. Moderately inhibits reuptake of serotonin an
norepinephrine. Although effective for bipolar disorder, the mechanism of action in bipolar
disorder is unknown.
40 mg PO bid with food on day 1, then increase to 60-80 mg PO bid on day 2; adjust dose
dult Dose according to tolerance and efficacy within range of 40-80 mg PO bid; not to exceed 3-wk
treatment duration
ediatric Dose Not established
ontraindications Documented hypersensitivity; history of prolonged QT interval
CYP450-3A4 inhibitors (eg, erythromycin, ketoconazole) may increase serum levels; CYP450-
3A4 inducers (eg, carbamazepine, rifampin) may decrease serum levels; coadministration with
nteractions drugs that increase QT/QTc interval (eg, amiodarone, fluoroquinolones) increases risk of life-
threatening arrhythmias; amphetamines may decrease efficacy of ziprasidone; ziprasidone may
decrease efficacy of levodopa
regnancy C - Safety for use during pregnancy has not been established.
Prolongs QT/QTc interval (caution in patients with known risk factors, eg, hypomagnesemia,
hypokalemia); caution in seizure disorders; may cause hypotension, extrapyramidal symptoms,
recautions
and somnolence; hyperglycemia may occur and in some cases be extreme, resulting in
ketoacidosis, hyperosmolar coma, or death

omplications:

• The complications are suicide, homicide, and addictions. These are discussed in Special Concerns.

rognosis:

• Patients with BPI fare worse than patients with a major depression.
• Within the first 2 years after the initial episode,
• 40-50% of patients experience another manic attack.

• Only 50-60% of patients with BPI who are on lithium gain control of their symptoms.
• In 7% of these patients, symptoms do not recur.
• Forty-five percent of patients experience more episodes
 • and 40% go on to have a persistent disorder.

• Often, the cycling between depression and mania accelerates with age.

• Factors suggesting a worse prognosis include the following:

o Poor job history

o Alcohol abuse
o Psychotic features

o Depressive features between periods of mania and depression

o Evidence of depression
o Male sex

• Indicators of a better prognosis include the following:

o Manic phases (short in duration)

o Late age of onset
o Few thoughts of suicide
o Few psychotic symptoms

o Few medical problems

atient Education:

• Treatment of patients with bipolar disorder involves initial and ongoing patient education.
• The educational efforts must be directed not only toward the patient but also toward their family and support system.
• Furthermore, evidence continues to mount that these educational efforts not only increase patient compliance and their knowledg
• but also their quality of life (Dogan, 2003).

o First, an explanation of the biology of the disease must be provided.

o This lessens the guilt and promotes medication compliance.

o Second, include information about how to monitor the illness in terms of an

o appreciation of the early warning signs,
o reemergence,
o And symptoms.
o Recognition of changes can serve as a powerful preventive step.

o A strong therapeutic alliance remains an essential part of treatment and education.

o Education also must encompass the dangers of stressors.

o Helping the individual identify and work with stressors provides a critical aspect of patient and family awareness.

o Finally, inform the patient about relapses within the total context of the disorder.

ddress factors that facilitate relapses( Substance use, Dangers of Stressors, Role of Medication)

pecial Concerns:

• Several special concerns accompany patients with bipolar disorder, including suicide, homicide, and addiction.

o Suicidal patients remain at risk for suicide. Patients emerging from a depression are thought to be at an increased risk fo
 death is lifelong. Hong's 2003 study demonstrates a genetic link between bipolar disorder and suicidal behavior, especial

o Homicidal patients, often in the manic phase, can be very demanding and grandiose. In this context, they will be angered
wishes. This can make them turn dramatically violent. Also, they can become homicidal by acting on delusions.

o Individuals with bipolar disorder are at risk for an addiction. This creates the problem of a dual diagnosis and, therefore, c