Bipolar Disorder: What s the Difference & What s New?

Bipolar Disorder:

What’s the Difference &

What’s New?

Rex S. Lott, Pharm.D., BCPP

Professor, Idaho State University College of Pharmacy

Mental Health Clinical Pharmacist, Boise VA Medical Center Clinical Associate Professor, University of Washington, School of Medicine, Department of Psychiatry & Behavioral Sciences

I have no relevant financial interests with respect to this subject

Learning Objectives for

Pharmacists

• Describe the differences in appropriate

pharmacotherapy for bipolar depression as

compared to unipolar depression

• Identify significant patient education points

for a specific “mood stabilizing” medication

• Recognize potential drug interactions related

to a specific “mood stabilizing” medication

and describe potential management or

Learning Objectives for Technicians

• State common signs and symptoms and the

usual course of an episode of mania and bipolar

disorder

• Identify medications used for treatment of

mood episodes in bipolar disorder

• Recognize the common side effects associated

with “mood stabilizing” medications and those

that indicate need for referral of a patient to a

pharmacist or other health-care provider

Bipolar Disorder:

• One or more episodes of:

– Mania

– Hypomania

– Mixed episodes

• Depressive episodes may / may not have

occurred --- YET

Bipolar Disorder: Sub-Types

• Bipolar I: manic or mixed episodes.

• Bipolar II: hypomanic episodes.

• Cyclothymic Disorder: Chronic (



2 years)

fluctuation between subsyndromal

depression (“dysthymia”) and hypomania

• Rapid Cycling: > 4 mood episodes in 12

Mania: Diagnostic Criteria

• Distinct period of persistently & abnormally

elevated, expansive, or irritable mood

– At least 1 week OR hospitization needed

• At least 3 persistent, significant symptoms:

– Inflated self-esteem / grandiosity – Decreased need for sleep

– Pressured speech

– Flight of ideas / “Racing Thought” – Distractibility

– Increased goal-directed activity / “agitation” – Excessive pleasurable activities with high risk

Mania: Diagnostic Criteria (ctd)

• NOT mixed episode

• Severe – marked impairment of functioning

– Occupational – Social

– Psychotic features (hallucinations, delusions, etc.) – Requires hospitalization

Hypomania

• Similar, but milder symptoms

• 4 – 7 days duration, OR

• NO IMPAIRMENT in functioning

• NO psychotic symptoms

• Stereotype of mania – “All of the fun &

none of the pain.”

DIGFAST

Symptoms of Hypomania/Mania

D

I

G

F

A

S

T

sexual, financial, travel, driving, etc.

Mixed Episode

• Dysphoric mania / Euphoric depression

• SIMULTANEOUSLY meet criteria for

depression (except duration) AND mania

nearly every day for 1 week

• Fluctuating presentation with rapidly

alternating symptoms

• Results in DX of Bipolar I Disorder

Bipolar Disorder: Course

• Adolescent to young adulthood onset

• 75% report mulitple depressive episodes

before 1

manic episode

• ~ 70% mis-diagnosed (often as unipolar

depression)

• ~ 35% wait at least 10 years for first

accurate DX

Bipolar Disorder: Course

• Despite treatment:

– ~ 70+% - recurrence within 5 years. – ~ 50% - ongoing symptoms

– # of episodes correlates with residual symptoms between episodes and TX response

– ~ 20% - euthymic

• Complications:

– Higher overall mortality (cardiovascular)

– Untreated mania: Confusion, exhaustion, fever, fatality – High Suicide Risk

Bipolar Disorder Treatment:

Acute Mania/Mixed Episode

• Hospitalization

• Rapid, aggressive pharmacotherapy

– IM or PO antipsychotics +/- benzodiazepine (lorazepam)

• Haloperidol

• Ziprasidone (Injectable Not FDA – approved for mania) • Olanzapine (Injectable approved for mania)

• Aripiprazole (Injectable approved for mania)

– Lithium combined with IM or PO antipsychotics – “Loading Doses” of valproate

• Mixed episodes • Rapid cycling

– Oral carbamazepine SR (Equetro®₎

Mania: Acute Treatment

• Several International Guidelines Recently Updated • Overall, fairly open and non-restrictive – little added

“wisdom”

• 1st _{Line Monotherapy with ANY drug classified as a}

“mood stabilizer”

• Lithium (Li)

• Valproic acid/Divalproex (VPA)

• Antipsychotics (usually 2nd _Generation)

• Carbamazepine (Controversial as monotherapy) • Benzodiazepines concurrently if needed

• Two-Drug Combination often used

• Li or VPA + Atypical Antipsychotic • NOT 2 atypicals

Mania: Acute Treatment (Ctd.)

• 3rd _Line:

– Switch to different 2-drug combination – Electro-Convulsive Therapy (ECT)

– Add Clozapine or add atypical antipsychotic to Li + other mood stabilizer

•

NOT RECOMMENDED:

– Monotherapy with gabapentin, topiramate or lamotrigine.

Mixed Episodes / Rapid Cycling

• Li not considered first line choice

• Generally less likely to be effective

Bipolar Disorder:

Hypomania

• Often don’t seek treatment unless depressed

• Initiation of mood stabilizer with psychotherapy

– GOAL: RELATIVELY QUICK CONTROL OF SYMPTOMS – Prevention of progression/switch to mania (??)

Bipolar Disorder: Depression

• Depressive episodes more common

• Mood stabilizers rather than antidepressants

– Lithium

– Quetiapine – Valproate

– Carbamazepine – Lamictal

• At minimum: Mood stabilization before initiation

of antidepressant therapy

Bipolar Depression

First Line (depends on recent history of mania)

• Li (0.8 mEq/L), Quetiapine, Olanzapine-Fluoxetine • SSRI with mood stabilizer

• Valproate

• Valproate + bupropion • Lamotrigine (?)

Stage 2 and beyond (NOT well characterized):

• Combinations of first-line approaches

• “Augmentation”: Pramipexole, modafanil • MAOI’s

• ECT

Approach to Treatment of

Bipolar Depression

• BP I disorder: optimize mood stabilizer, particularly those with AD properties (lithium, lamotrigine,

quetiapine)

• FDA-approved agents for bipolar depression: quetiapine and olanzapine/fluoxetine

• Assess candidacy for antidepressants

– BP II>I; no mixed features; no rapid cycling; no substance

abuse; no recent mania; no history of antidepressant induced mania

• Consider ADs studied in bipolar depression over those which have not; avoid those with negative data

No Advantage for Antidepressant (AD) + Mood Stabilizer (MS) vs. Mood Stabilizer + Placebo for Bipolar Depression:

STEP-BD 0 5 10 15 20 25 30 MS + AD (N=179) MS + PBO (N=187) % wi th Du rab le Rec overy 23.7 % 27.1 % AD=Paroxetine up to 30 mg/day or bupropion up to 300 mg/day

Antidepressants Studied in Randomized

Controlled Trials for Bipolar Depression

Studied Not Studied

Bupropion Duloxetine

Venlafaxine Desvenlafaxine

Sertraline Citalopram/Escitalopram

Paroxetine Fluvoxamine

Fluoxetine (BP II; or w/OLZ) Mirtazapine

Tranylcypromine Transdermal Selegiline Desipramine, Imipramine

Summary

• AD-induced mania/hypomania occurs in ~ 10-15% of patients with bipolar disorder

• ADs are not that effective for bipolar depression. No study has ever shown an advantage for an AD over placebo in the presence of a mood stabilizer

• ADs can prevent recurrent depression in bipolar disorder in those patients with a robust acute response

• Noradrenergic ADs appear to be more prone than other ADs to cause mania/hypomania

• Co-therapy with antimanic drugs does not seem to reliably prevent AD-induced mania/hypomania.

Bipoloar Disorder: Maintenance

Treatment

• Most patients with bipolar disorder require

indefinite maintenance treatment to reduce

risk of / severity of recurrent mood episodes

• Adherence education

• Monitoring for and assisting with side effects

• Monitoring for and assisting with potential

Lithium

• Advantages:

– Well-studied – Effective

– Reduces risk of suicide****** – Cheap

• Disadvantages

– Intolerance of adequate doses by many – Risk of intoxication

– Slow onset of effect (dynamics vs kinetics)

Lithium Plasma Concentrations

• Approx 3 – 5 days to steady state

• Blood sampled 12 hours after last dose

• TARGETS:

– 0.5 – 1.5 mEq/L ROUGHLY

• Patient tolerance

–  0.8 mEq/L for depression

Lithium Intoxication

• USUALLY: > 1.5 mEq/L

– Variability

• Increasing GI Effects: N V D

– Dehydration, electrolyte imbalance, decreased lithium elimination

• Increasing (“Coarsening”) tremor

• Ataxia, slurred speech

• Confusion, disorientation

• Seizures, coma, death

Lithium: Side Effects

• Education Points

– GI Discomfort: N,V,D

• With food

– Tremor – with “therapeutic” doses

– Worsening tremor as sign of intoxication – Potential for weight gain (~25% of patients) – Polyuria, polydipsia early in therapy

Lithium: Education Points

• AVOID:

– Sudden changes in diet ( intake) – Sodium restriction / diuretics

– Dehydration (maintain fluids)

– OTC NSAIDs without discussion with MD or Pharm.D. – Increases (changes!!) in caffeine (xanthine) intake

Lithium: Monitoring

• Thyroid function:

• Parathyroid function

• Renal function

–  renal function =  dosage requirements – Lithium-induced renal dysfunction???????

• Urine output: Risk of Lithium-induced

Lithium Drug Interactions

• ORDER OF ADMINISTRATION OFTEN CRITICAL

• Xanthines: Theophylline, caffeine, theobromine, etc

– Increase lithium renal clearance

• NSAIDS (



GFR)

• THIAZIDE – type diuretics and other non- “Loop”

Diuretics

– Do not increase lithium excretion

– Compensatory sodium and lithium reabsorption

Valproate = VPA

Valproic Acid = Depakene

®

Divalproex:

Depakote

®

, Depakote Sprinkles

®

,

VPA: DOSING

• Reasonable Target Maintenance Dose

– 20 mg/kg/day (1500 – 2000 mg/day)

• Loading Dose for Acute Treatment:

– 20 mg/kg on day 1 in 2-3 divided doses

• With food

• Depakote/Depakote ER

– Should not be crushed or split – May need increased doses

– Depakote ER dose = ~ 120% of VPA or Depakote

• Depakote Sprinkles can be opened and mixed

with food.

35

VPA Common Side Effects:

• GI: Nausea, heartburn, diarrhea

– Give with food

– Switch to Depakote if necessary

• Sedation: Usually transient at start of treatment or with increased dose

• Weight Gain: Common, can be dramatic

• Tremor: Intention tremor (usually not Parkinsonian)

– Similar to lithium tremor – Propranolol

36

VPA Common Side Effects: (cont.)

• Hair Loss:

– Usually temporary

• Reduced platelet counts:

– High doses/plasma levels

– Minimal/absent bleeding complications – Reversible with dose reduction

• Elevated liver enzymes (ALT/AST):

– Early in therapy; usually asymptomatic & mild – Temporary dose reduction; time

37

VPA: Serious Adverse Effects:

• Hepatotoxicity

– Significant elevation in LFTs with abdominal pain, vomiting, jaundice, coagulation deficiencies

– Exceedingly uncommon in adults who are not taking other AEDs

• Probably due to toxic metabolite

– Pre-existing liver disease (e.g., Hepatitis C) NOT necessarily a contraindication

38

VPA: Drug Interactions

• Potent Inhibitor of Hepatic Metabolism of

other medications

– Lamotrigine

– Tricyclic Antidepressants (e.g., Imipramine) – Phenytoin (Dilantin®₎

– Phenobarbital

– Carbamazepine – 10,11-epoxide (active metabolite of carbamazepine)

39

VPA Drug Interactions (cont.)

• VPA metabolism increased significantly by

enzyme-inducing drugs

• Carbamazepine • Phenytoin

• Phenobarbital

• Ethanol (in sober patients)

– Increased dosage requirements for VPA for equivalent response

Other “Mood Stabililzers”

• Carbamazepine

– Potent hepatic enzyme inducer; decreases effectiveness of other meds

• Oral Contraceptives • Quetiapine

• Oxcarbazepine

– Less potent hepatic enzyme inducer. Still significant effects on oral contraceptives

Other “Mood Stabilizers” (ctd.)

• 2

_{Generation (“Atypical) Antipsychotics}

– Most approved for acute mania

– ALL being used for acute mania and for maintenance therapy.

– Weight gain, diabetes precipitation/aggravation

• NOT ziprasidone

• LESS with aripiprazole and probably lurasidone

Assessment Questions for

Pharmacists

Which antidepressant appears less likely to precipitate mania or hypomania when it is used in patients with

bipolar depression?

A. Paroxetine (Paxil)

B. Amitriptyline (Elavil)

C. Bupropion (Wellbutrin)

D. No difference

Weight gain and potential metabolic complications such as worsening diabetes should be discussed with patients taking which of the following mood stabilizing medications?

A. Lithium

B. Quetiapine

C. Valproate (valproic

acid or divalproex)

D. All of the Above

Patients with bipolar depression are most likely to have a therapeutic antidepressant response to:

A. Fluoxetine

monotherapy

B. Imipramine

monotherapy

C. Quetiapine

monotherapy

D. Imipramine + mood

stabilizer

Assessment Questions for

Technicians

Which of the following symptoms is

characteristic of mania?

A. Decreased need for

sleep

B. Pressured speech

C. Inflated self-esteem

D. Increased

goal-directed activities

E. All of the above

Which of the following medicines is used for the treatment of mania or hypomania in bipolar disorder?

A. Fluoxetine (Prozac)

B. Quetiapine (Seroquel)

C. Imipramine

Which of the following side effect complaints by a patient taking lithium would may indicate early lithium

intoxication?

A. Worsened or “coarse”

hand tremor

B. Gait disturbance (e.g.,

staggering)

C. Slurred speech

D. All of the above