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Bipolar Disorder: Lessons for Rural Physicians: Adjunctive Interventions for Maintaining Remission Steven Bander, DO, FACOFP Bander Family Medical Center Wylie, Texas Disclosure • Nothing to disclose Objectives • Recognize the importance of utilizing guideline recommendations during maintenance treatment of patients with bipolar disorder • Develop a maintenance treatment plan for patients with bipolar disorder based on guidelines • Systematically monitor effectiveness and safety of maintenance treatment Epidemiology of Bipolar Disorder • Lifetime prevalence rate is 0.7 to 1.6% • Gender prevalence is equal for Bipolar I disorder • Bipolar II and rapid cycling more common in women • First degree relatives 24 times more likely to develop bipolar disorder • Concordance rate 79% in MZ twins and 19% in DZ twins • Average onset age 21 Bill J • Bill J. is sent by his employer for a fitness-for-duty exam. He has been talking almost continuously for days, sexually propositioning his supervisees, and bursting into his boss’ office repeatedly with a “plan to save the company.” He has worked there for 12 years and generally been a good employee. There is no history of psychiatric illness. He talks non-stop during his interview with you and seems grandiose but not psychotic. States he really does not need sleep. His physical exam is essentially normal. Patients With Bipolar Disorder Are Symptomatic for Almost Half of Their Lives Weeks asymptomatic Weeks manic/hypomanic 9% 32% Weeks depressed Weeks cycling/mixed 6% 53% N = 146 12.8 years follow-up Judd LL, et al. Arch Gen Psychiatry. 2002;59:530-537. Bipolar I Disorder: Diagnosis • Single manic episode • One manic or mixed episode (in patient’s history) • Recurrent • Current Manic, Major Depressive, Mixed, or Hypomanic episode • Previous Manic, Major Depressive, or Mixed episode • Relapsing and remitting course • Major Depressive Episodes have usually occurred but are not required for the diagnosis • The mood symptoms are not better accounted for by a Psychotic Disorder including Schizoaffective Disorder • Clear distinction between episodes and inter-episodic functioning • Often well or at least much better between episodes Clinical Features of Mania Mania • Behavioral Symptoms • Grandiosity, Diminished need for sleep, Pressured Speech, Excessive Libido, Recklessness, Impulsivity, Hostility, Violence • Affective Symptoms Hypomania • Euthymia • Depression, Anxiety, Euphoria, Irritability Psychotic Symptoms (Psychosis occurs in over 50% of manic episodes) • Hallucinations, Delusions, Sensory Hyperactivity • Cognitive Symptoms Dysthymia • Depression • Racing Thoughts, Distractibility, Poor Insight, Disorganization, Confusion, Inattentiveness, Suicidal Thoughts Suicide and Bipolar disorder (More likely in depressive or mixed episode) • 10-15% will complete suicide Manic Episode • Elevated, expansive, or irritable mood for 1 week • 3 or more of the following, 4 if irritable mood: (DTRHIGH) • • • • • • • Distractible Talkative or pressured speech Racing thoughts or flight of ideas Hyper-alert = decreased need for sleep Increased activity or psychomotor agitation Grandiose Hypersexual = risky acts • Severe enough to cause: • Marked impairment in functioning or Hospitalization (any duration of symptoms) or Psychotic features • Symptoms are not due to: • Substance or General medical condition Differential Diagnosis: Mania • General medical conditions • Head trauma, Mass lesions, Post-CVA, MS, Hyperthyroidism, Cushing’s, Huntington’s disease, complex partial seizures • Substance induced • Corticosteroids, levodopa, Stimulants: amphetamine, cocaine, ephedrine, Drug or Alcohol withdrawal syndromes, Antidepressants, ECT, light therapy • Schizophrenia, schizoaffective disorder • Psychotic symptoms occur in absence of mood symptoms • Borderline Personality Disorder • Similarities: impulsivity, suicidal behavior, irritability, paranoid ideation • Differences: enduring pattern, fear of abandonment, idealization/devaluation, identity disturbance, emptiness Bipolar I and II: Frequency of Depressive Symptoms Mixed 13% Depressed 67% Manic/ hypomanic 20% Bipolar I Patients with bipolar I disorder (n = 146) experienced mood symptoms 47.3% of the time during a 12.8-year follow-up period Depression 3.4-fold more frequent than mania Mixed 4.5% Manic/ hypomanic 2.5% Depressed 93% Bipolar II Patients with bipolar II disorder (n = 86) experienced mood symptoms 54% of the time during a 13.4-year follow-up period Depression 37-fold more frequent than mania Judd LL, et al. Arch Gen Psychiatry. 2002;59:530-537. Judd LL, et al. Arch Gen Psychiatry. 2003;60:261-269. Major Depressive Disorder • Relapsing and remitting course • May eventually become chronic • Minimum duration ≥ two weeks • Clear distinction between episodes and interepisodic function • Often well or at least much better between episodes Clinical Features of Depression Mania • Affective Symptoms • Depressed mood (sad, down, blue) • Reduced interest or pleasure • Cognitive Symptoms Hypomania Euthymia • Poor concentration/easy distraction • Inappropriate guilt/self reproach • Thoughts of death, dying, suicide • Behavioral Symptoms • • • • Change in appetite Change in sleep pattern Reduced energy level Psychomotor agitation/retardation • Suicide and Bipolar disorder (More likely in depressive or mixed episode) • 10-15% will complete suicide Dysthymia Depression Clinical Features: Major Depression • 5 or more of these for 2 weeks: (SIGECAPS) • • • • • • • • • Depressed mood most of the day Sleep decreased or increased Interests decreased Guilt (excessive) or worthlessness Energy decreased Concentration decreased or indecisive Appetite change or weight change Psychomotor retardation or agitation Suicidal ideation or attempt Differential Diagnosis: Depression • Psychiatric • Adjustment D/O • Bereavement • General Medical • Hypothyroidism, Anemia • Post-CVA, Post-MI • Ca of head of pancreas • Substance-Related • Rx meds: steroids, b-blockers, a-methyldopa • Alcohol or Benzodiazepine abuse • Cocaine/amphetamine withdrawal Clinical Features of Mixed Episode Mania Hypomania Euthymia • Full symptoms of manic and major depressive episodes for 1 week • Severe enough to cause: • Marked impairment in functioning • Or • Hospitalization • Or • Psychosis Dysthymia • Symptoms are not due to: Depression • Substance • General medical condition Clinical Features of Rapid Cycling Mania Hypomania Euthymia Dysthymia Depression • 4 or more mood episodes in 12 months • Major depressive, manic, mixed, or hypomanic episodes • Separated by: • Remission for 2 months or • Switch to opposite polarity Clinical Features of Bipolar II Mania Hypomania Euthymia Dysthymia Depression • Current or past Major Depressive episode • Current or past Hypomanic episode • Never a Manic or Mixed episode • Not a primary psychotic disorder • Clinically significant distress or impairment in functioning Clinical Features of Hypomania Mania Hypomania Euthymia • Different from usual mood • Clear change in functioning • Observable by others • Does not cause: • Marked impairment in functioning • Hospitalization • Psychotic features Dysthymia • Symptoms are not due to: Depression • Substance • General medical condition Hypomanic Episode • Elevated or irritable mood for 4 days • 3 or more of the following: (DTRHIGH) • • • • • • • Distractible Talkative or pressured speech Racing thoughts or flight of ideas Hyper alert = decreased need for sleep Increased activity or psychomotor agitation Grandiose Hypersexual = risky acts Co-morbid Psychiatric Conditions • Alcohol and drug abuse/dependence • Most common co morbid condition • Worse prognosis • Must treat concurrently • Personality disorders • Anxiety disorders • ADHD Always ask about mania before treating depression Goals of Treatment • Symptomatic Remission • Full return of psychosocial functioning • Prevention of relapses and recurrences J Clin Psychiatry 66:7 July 2005 Setting the Stage for Treatment • Engage the patient in the Treatment Plan – Discuss the Diagnosis – Discuss the treatment options • Engage appropriate significant others in the Treatment Plan – With the consent of the patient • Encourage the patient to keep a daily mood log • Encourage the patient to engage in therapy – Psychoeducational – Cognitive Therapy J Clin Psychiatry 66:7 July Evidence Based Treatment • These recommendations for treating Bipolar Disorder are based on: • TIMA Algorithm for Bipolar • Texas Implementation of Medication Algorithms (TIMA) • APA Treatment Guidelines for Bipolar • American Psychiatric Association Algorithm – Mania Symptoms • Treating Acute Hypomanic/Manic/Mixed Episodes of Bipolar I Disorder • Monotherapy (Euphoric) • Lithium, valproate, aripiprazole, quetiapine, risperdone, ziprazidone • No response: olanzapine, carbamazepine • Monotherapy (mixed) • valproate, aripiprazole, risperdal, ziprazidone • No response: olanzapine, carbamazepine Algorithm • If monotherapy fails (two drug combinations) • lithium, valproate, or atypical antipsychotic • Note: not two atypical antipsychotics and not aripiprazole or clozapine • If partial or no response • lithium, valproate, atypical antipsychotic, carbamazepine, oxcarbazepine, typical antipsychotic • Note: not two atypical antipsychotics and not clozapine Algorithm – Depressive Symptoms • Treating Acute Depressive Episodes in Patients with Bipolar I Disorder • To begin this algorithm we must establish some key facts: • A patient taking lithium (increase to 0.8 mEq/L), or • A patient is taking another antimanic medication, or • Patient is not taking any antimanic medication and has a history of severe and/or recent mania • The treatment step would be to provide the patient with an antimanic medication and lamotrigine Algorithm – Depressive Symptoms • You may have a patient without a history of severe and/or recent mania and is not taking any antimanic medication • The treatment step would be to provide the patient with lamotrigine Algorithm – Depressive Symptoms • The previous 2 slides outlined Stage 1 of the TIMA algorithm for Treating Acute Depressive Episodes in Patients with Bipolar I Disorder • If there was only partial or non-response to stage 1 interventions taper off any medications that need tapering and start a monotherapy of • quetiapine or an olanzapine-fluoxetine combination Algorithm – Depressive Symptoms • If there was only partial or non-response to stage 2 interventions and start a combination therapy of any two of the following medications • lithium, lamotragine, quetiapine or an olanzapine-fluoxetine combination • Consider consultation if this fails FDA Approved Drugs • FDA Approved Drugs for Mania • Aripiprazole • Carbamazepine • Chlorpromazine • Divalproex • Lithium • Olanzapine • Quetiapine • Risperidone • Ziprasidone • FDA Approved Drugs for Bipolar Depression • Olanzapine-Fluoxetine Combination • Quetiapine Definition of a Mood Stabilizer • • • • Treats acute depression and/or mania Reduces risk of relapse of mania and/or depression Does not increase risk of mania Does not increase risk of depression Rationale for lithium salts as the Mood Stabilizer of First Choice • • • • • Track record (dating to 1960s) Evidence of efficacy Well-characterized tolerability and safety profiles Low cost Evidence of reduction of suicidal behavior Lithium Carbonate • FDA approved for acute mania and maintenance • Workup • Beta-HCG, BUN, creatinine, thyroid profile, EKG • Serum levels • Acute mania=1.0-1.5 meq/L • Maintenance=0.6-1.2 meq/L • Toxicity at above 1.5 meq/L Lithium Carbonate • Pregnancy • First trimester: cardiac defects • Toxicity • Narrow therapeutic index • Nausea, vomiting, blurred vision, vertigo, confusion, seizures, coma • Lithium level increased by: • Low serum sodium, Diuretics, ACE inhibitors, NSAID’s • Excreted by kidneys Lithium: Adverse Effects • Diuretics (e.g., thiazides) can reduce lithium clearance by as much as 25% -Preferentially eliminate Na+ • NSAIDs can reduce lithium clearance. • Worsens extrapyramidal syndromes produced by older antipsychotic drugs. • Side Effects and their management • Begin with dose decrease • Tremor - propranolol • Polyuria - amiloride • Hypothyroidism – levothyroxine -TSH every 6-12 months • G.I. Distress - take with food, change to lithium citrate • Cardiac: T-wave & conduction changes • Mild cognitive impairment • Transient acneiform eruptions • Leukocytosis Efficacy of Lithium: All Relapse Geddes JR, et al. Am J Psychiatry. 2004;161(2):217-222. Valproic Acid • Formulations • Valproic acid • Sodium valproate • Divalproex sodium=combination of both • Compared to lithium • Faster onset of anti-manic effects • Better for mixed episodes & rapid cycling • Wide therapeutic window Valproic Acid • Side Effects and their management • • • • • • • Elevated hepatic transaminases - monitor LFT’s Rare hepatotoxicity Leukopenia - monitor WBC G.I. Distress - decrease dose, try divalproex Sedation - give more at bedtime Weight gain - diet & exercise Hair loss - zinc, selenium Valproic Acid • Pregnancy • First trimester - neural tube defects, craniofacial abnormalities • Therapeutic serum level • 50-125 mcg/mL • Workup • Beta-HCG, CBC + differential, liver function tests (LFT’s) Rationale for status of Divalproex • Efficacy comparable to lithium • Useful in patients who do not respond to or don’t tolerate lithium • More useful than lithium for patients with mixed affective states and significant substance abuse histories • Vigorously marketed, without opposition, from 19942002 Market Share Shifts in Prescription of Lithium and Divalproex Total N: 20,638 Goodwin, et al. JAMA 2003;290:1467-1473 Carbamazepine • Side Effects • • • • • Sedation, weight gain Dermatitis, rashes G.I. Distress Dizziness, ataxia, diplopia Leukopenia, LFT elevations • Rare, but serious • Agranulocytosis, aplastic anemia • Exfoliative dermatitis (Stevens-Johnson syndrome) • Hepatic failure Carbamazepine • Pregnancy • First trimester - neural tube defects • Drug-drug interactions • Induces metabolism and decreases levels of: • Carbamazepine (auto-induction), valproic acid, lamotrigine, oral contraceptives • Therapeutic serum level • 4-12 mcg/mL • Workup • CBC + differential, platelets, liver function tests Lithium, Divalproex or Carbamazepine, Risk of Suicidal Behaviors Advantage for Lithium vs. DVPX vs. CARB Suicide attempts: ER 1.8 (1.4–2.2)* 1.4 (1.0-2.0) Suicide attempts: Admission 1.7 (1.2-2.3)* 2.9 (1.9-4.4)* Suicide attempts: Death 2.7 (1.1-6.3)* 1.5 (0.3-7.0) Goodwin, et al. JAMA 2003;290:1467-1473 Lamotrigine • Not effective in acute mania • Lamotrigine is especially effective against depression (Bowden et al 2003) • Effective for bipolar depression • Serious side effect • Stevens-Johnson syndrome • Discontinue if rash occurs • Use slow titration • Drug-drug interactions • Valproic acid inhibits metabolism & doubles serum concentration • Carbamazepine induces metabolism and halves serum concentration Second Generation Antipsychotic Safety and Tolerability Concerns • Weight gain • ± Akathisia • Sedation • ± Hyperprolactinemia • Diabetes • Cerebrovascular (elders) • Cardiac Olanzapine • FDA approved for acute mania • Side effects • Sedation • Weight gain • Elevated hepatic transaminases Quetiapine • FDA approved for acute mania • Side effects • Sedation • Orthostasis (during titration) Risperidone • FDA approved for acute mania • Side effects: at higher doses • Extrapyramidal symptoms • Elevated serum prolactin Antidepressants • Use in bipolar depression • Concurrent with mood stabilizer • Some cause switch to mania • Tricyclic antidepressants & venlafaxine • Bupropion and paroxetine have low rate of switch to mania Adjunctive medications • Antipsychotics • Use when psychosis is present • Taper and discontinue when psychosis resolves • Benzodiazepines • Lorazepam, clonazepam • Use in severe mania as a short term sedative Electroconvulsive therapy • Highly effective treatment • Acute illness and maintenance treatment • Indications • Severe or refractory mania or depression • Psychosis with depression or mania • Patient cannot tolerate medication Other Mood Stabilizers: Antipsychotics or Benzodiazepines • Antipsychotics • Including: olanzapine, haloperidol, risperidone, quetiapine, ziprasidone, and aripiprazole • Primarily used for controlling acute mania. • Clonazepam or Lorazepam • Benzodiazepines may be given to control acute mania (often as an adjunct to treatment with an antipsychotic drug or other mood stabilizing drug, be cautious of disinhibition). Combination Therapy Average Number of Medications in 258 Bipolar Outpatients Followed Up Prospectively for 1 Year 60 Number of Patients 20.9% 50 18.2% 17.1% 40 12.0% 30 20 12.0% 6.6% 6.6% 10 3.1% 1.9% 0.8% 0.8% 0 0 1 2 3 4 5 6 7 8 9 10 Total Number of Medications Post RM, et al. J Clin Psychiatry. 2003;64(6):680-690. Pros and Cons of Combination Therapy FOR • 40% of patients do not respond to monotherapy • Lower doses improved tolerability AGAINST • Drug interactions • Suboptimal dosing of both agents • More complex treatment regimen • Decreased adherence • Increased side effects • Cost Bowden 2004; Goodwin & Vieta 2005 Goal of Treatment: Mood Stabilization Mania Mood stabilizers • Effective in the acute treatment or stabilization of manic/mixed, hypomanic, and depressive episodes Hypomania Euthymia • Do not induce alternate mood symptoms (ie, switch) • Prevent against future relapse or recurrence of manic/mixed, hypomanic, or depressive symptoms or episodes Dysthymia Depression Visit Timelines • • • • • First Week Third Week Monthly for at least 3 months Then Every 2-3 months thereafter When the patient has been stable for 4 to 6 months (engage the patient via phone or contact with non-physician clinicians) Therapeutic Challenges • • • • No cure for bipolar disorder Noncompliance rate is high Symptom overlap among comorbid diagnoses Longer Term Efficacy • Across symptom domains • Definition of a mood stablizer • Safety and tolerability Managing Complex Medication Regimens • Try to ensure that at least 1 medication is a mood stabilizer • Understand that side effect burden is additive • Periodically review the need for all medications Recommended Options for Acute Treatment of “Breakthrough” Bipolar Depression • • • • Optimization of mood stabilizer (MS) Addition of second MS or SGA Addition of antidepressant to MS Addition of focused Psychotherapy to MS How long should antidepressants be continued? What do we do when there’s no consensus? • Expert recommendations for duration of antidepressant therapy range between “8–12 weeks” and “indefinite-lifetime” Role of Psychotherapy in Bipolar Disorder • If effective for depression, avoids pharmacologic risk of TEAS • Only 1 controlled study of acute phase therapy (conducted as part of STEP-BD) • Preferred option for many patients • Relapse prevention and adherence-enhancing effects demonstrated for CBT, FFT, and IPSRT TEAS=treatment emergent affective switch. CBT=cognitive behavioral therapy. FFT= functional family therapy. IPSRT= Interpersonal and Social Rhythm Therapy. STEP-BD=Systematic Treatment Enhancement Program for Bipolar Disorder. Miklowitz DJ, et al. Arch Gen Psychiatry. 2007;64(4):419-426. Importance of Treatment Adherence • Most people with bipolar disorder will have periods of non-adherence to therapy • Abrupt discontinuation of medications hastens relapse • Ask about adherence at each visit! • Keep track of prescription refills Factors Frequently Associated With Noncompliance in Bipolar Patients • • • • • • • • • Young age Male gender Being unmarried Multiple medication regimens Fewer episodes First year of lithium treatment History of manic episodes Comorbid psychiatric illness Substance abuse The Fundamental Factor in Long-Term Outcome in Bipolar Disorder • Being in a treatment relationship • Inadequate treatment associated with adverse outcomes (e.g., use of antidepressants alone) • Treatment per se, even with placebo, improves outcomes, including reduced suicidality • Not being in treatment increases costs, principally by higher rates of hospitalization, emergency care Begley CE et al. (2001), Pharmacoeconomics 19(5 pt 1):483-495, Angst F et al. (2002), J Affect Disord 68(2-3):167-181; Yerevanian BI et al. (2003), J Affect Disord 73(3):223-228