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
Disclosure of Interests 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 avoidance strategies
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 Unipolar Mania uncommon
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 months (10% - 20%; more in females)
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 NOT due to substances or medical illness
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 Distractibility: poorly focused, multitasks I Insomnia: decreased need for sleep G Grandiosity: Inflated self-esteem F Flight of ideas: Complaints of racing thoughts A Activities; Increased goal-directed activities S Speech pressured; more talkative T Thoughtlessness; risk-taking behaviors sexual, financial, travel, driving, etc. Ghaemi SN. Primary Psychiatry. 2001;8(2):28-34
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 May be mis-understood as rapid cycling
Bipolar Disorder: Course Adolescent to young adulthood onset 75% report mulitple depressive episodes before 1 st manic episode ~ 70% mis-diagnosed (often as unipolar depression) ~ 35% wait at least 10 years for first accurate DX J Clin Psychiatry 2003;64:53
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 Med Clin Am 2001;85:645
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 ) GOAL: Symptomatic control ASAP
Mania: Acute Treatment Several International Guidelines Recently Updated Overall, fairly open and non-restrictive little added wisdom 1 st Line Monotherapy with ANY drug classified as a mood stabilizer Lithium (Li) Valproic acid/divalproex (VPA) Antipsychotics (usually 2 nd Generation) Carbamazepine (Controversial as monotherapy) Benzodiazepines concurrently if needed Two-Drug Combination often used Li or VPA + Atypical Antipsychotic NOT 2 atypicals NOT clozapine or aripiprazole
Mania: Acute Treatment (Ctd.) 3 rd 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. Nivoli AMA et al. J Affect Disord. 2011.
Mixed Episodes / Rapid Cycling Li not considered first line choice Generally less likely to be effective VPA, Antipsychotics, carbamazepine
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 (??) Reduction of recurrences of mood episodes
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 Olanzapine Fluoxetine Combination (Symbyax )
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 Suppes et al. J Clin Psychiatry 2005;66:870; Nivoli et al. J Affect Disord. 2010
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
% with Durable Recovery No Advantage for Antidepressant (AD) + Mood Stabilizer (MS) vs. Mood Stabilizer + Placebo for Bipolar Depression: STEP-BD 30 25 20 27.1 % 15 10 5 23.7 % 0 MS + AD (N=179) MS + PBO (N=187) Sachs et al., N Engl J Med 2007; 356: 1711-1722 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. Lithium appears more likely to be effective
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 drug interactions
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) Less effective for mixed episodes or rapid cycling
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 ~ 1.0 + meq/l for acute mania
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 Abrupt discontinuation of lithium
Lithium: Monitoring Thyroid function: Hypothyroidism / TSH common Parathyroid function Hypercalcemia / Hyperparathyroidism UNCOMMON Renal function renal function = dosage requirements Lithium-induced renal dysfunction??????? Urine output: Risk of Lithium-induced nephrogenic diabetes insipidus (L.I.N.D.I.)
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 ACE-I s & ARB s ( GFR)
Valproate = VPA Valproic Acid = Depakene Divalproex: Depakote, Depakote Sprinkles, Depakote ER
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.
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 35
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 36
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 Known Teratogen 37
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) 38
VPA Drug Interactions (cont.) VPA metabolism increased significantly by enzymeinducing drugs Carbamazepine Phenytoin Phenobarbital Ethanol (in sober patients) Increased dosage requirements for VPA for equivalent response POSSIBLE increased risk of VPA-related hepatotoxicity 39
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 nd 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 Relatively few drug-drug interactions
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 goaldirected 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 D. None of the above
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