bStable - Depression and Bipolar Disorder Disease State Management System - Presentation Slides
Bipolar Disorder: Review of Disease State and Treatment · 2018-04-01 · Bipolar Disorder: Review...
Transcript of Bipolar Disorder: Review of Disease State and Treatment · 2018-04-01 · Bipolar Disorder: Review...
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Bipolar Disorder:Review of Disease State
and Treatment
Marshall E. Cates, Pharm.D., BCPP, FASHP, FCCP
Professor of Pharmacy Practice
McWhorter School of Pharmacy
Samford University
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Learning Objectives
1. Describe the epidemiology, etiology/pathophysiology, clinical presentation and diagnosis, comorbidity, course and prognosis of bipolar disorder.
2. Discuss pharmacologic treatment options for bipolar disorder.
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Learning Objectives
3. Explain treatment approaches to bipolar disorder, including treatment of acute mania, treatment of acute depression, and long-term maintenance treatment.
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Introduction
• Mood – emotional state
• Mood episode – discrete period of mood disturbance
• Mood disorder – any of several mental disorders characterized by abnormalities of emotional state
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Euthymia
Mania
Hypomania
Subthreshold depression
Major depression
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Mood Episodes
• Manic episode – abnormally and persistently elevated, expansive, or irritable mood
• Hypomanic episode – less intense than mania; does not result in marked impairment in functioning, hospitalization, or psychosis
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Mood Episodes
• Major depressive episode –depressed mood or loss of interest or pleasure
• Mixed features can apply to any of the episodes – think of it as the presence of some symptoms from the opposite polarity
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Major
depressive
disorder
Bipolar I
disorder
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Bipolar Disorders
• Bipolar I disorder – one or more manic episodes (with or without a depressive episode)
• Bipolar II disorder – one or more hypomanic episodes and one or more major depressive episodes (but no manic episodes)
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Bipolar Disorders
• Cyclothymic disorder – at least 2 years of numerous periods of hypomanic symptoms (but no hypomanic episode) and numerous periods of depressive symptoms (but no major depressive episode)
• Others, such as substance-induced, medical conditions, etc.
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Epidemiology
• Lifetime prevalence approx. 1% for bipolar I disorder, 1% for bipolar II disorder, and 4-5% for entire bipolar spectrum
• Bipolar I disorder affects males and females equally; bipolar II disorder is more common in females
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Epidemiology
• Females with bipolar I or II disorder are more likely than males to experience depressive symptoms
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Etiology/Pathophysiology
• Genetic factors
– First degree relatives of patients have a 7-fold risk of developing the disorder
– Adoption studies show that risk is with biological rather than adoptive parents
– Twin studies show concordance rate of approx. 70% monozygotic vs. 20% dizygotic
• Stressful life events
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Etiology/Pathophysiology
• Neuroanatomical abnormalities
• Neurochemical abnormalities
• Second messenger system/signaling cascade dysregulation
• Neuroendocrine dysfunction
• Immune-mediated dysfunction
• Circadian dysfunction
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Clinical Presentationof Mania
• Elevated or euphoric mood
• Irritability
• Lability
• Increased energy or hyperactivity
• Decreased need for sleep
• Increased or pressured speech
• Distractibility
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Clinical Presentationof Mania
• Racing thoughts or flight of ideas
• Grandiosity
• Delusions and/or hallucinations
• Demanding, threatening, or aggressive
• Impulsivity
• Garish appearance
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Diagnosis of Manic Episode
• Mood = elevated or irritable (and increased energy or activity)
• Time frame = at least 1 week
• Symptoms = at least 3 of DIG FAST (next slide)
• Impairment in functioning, need for hospitalization, or presence of psychotic symptoms
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DIG FAST
• D distractibility
• I involvement/indiscretion
• G grandiosity
• F flight of ideas
• A agitation/activity
• S sleep (decreased need)
• T talkativeness
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Clinical Presentationof Depression
Emotional
• Sadness
• Anxiety
• Guilt
• Irritability
• Anger
• Feelings of hopelessness or helplessness
Physical
• Fatigue
• Sleep disturbance
• Appetite/weight changes
• Decreased libido
• Aches and pains
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Clinical Presentationof Depression
Cognitive/Perceptual
• Poor concentration
• Slowed thinking
• Indecisiveness
• Impaired memory
• Self-criticism
• Suicidal thoughts
• Delusions
• Hallucinations
Behavioral
• Crying
• Social withdrawal
• Psychomotor changes
• Neglect of responsibilities
• Changes in appearance
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Diagnosis of Major Depressive Episode
• Mood = depression or anhedonia
• Time frame = at least 2 weeks
• Symptoms = at least 5 of SIG E CAPS (next slide); 1 must be either depressed mood or anhedonia
• Clinically significant distress or impairment in functioning
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SIG E CAPS
• S sleep (↑↓)
• I interest (↓)
• G guilt/worthlessness
• E energy (↓)
• C concentration (↓)
• A appetite (↑↓)
• P psychomotor (↑↓)
• S suicidality
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Differential Diagnosis
• Major depressive disorder
• Anxiety disorders
• Substance use disorders
• ADHD
• Personality disorders
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Comorbidity
• Anxiety disorders
• ADHD
• Disruptive, impulse-control, and conduct disorders
• Substance use disorders
• Serious and/or untreated medical conditions
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Course
• Often a substantial delay between onset of illness and diagnosis
• Misdiagnosis is very common early in the illness
• Onset usually late adolescence to early adulthood; onset of mania after age 60 is more likely to be due to medical conditions or substances
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Course
• Commonly a chronic relapsing and remitting condition
• Highly recurrent
– 90% have at least 2 episodes
– 80% have > 4 episodes
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• More than one-half of manic episodes occur immediately before a depressive episode
• Some patients continue to experience residual mood symptoms and functional impairment between episodes
Course
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Course
• Acceleration of episode frequency is common
• Rapid cycler – > 4 mood episodes per year
– Approx. 10-20% of patients
– Women > men
– Poorer prognosis; more difficult to treat
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Prognosis
• Mortality
• Suicide
• Substance abuse
• Employment difficulties/disability
• Divorce
• Financial/legal problems
• Medication nonadherence
• Hospitalization
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Question #1
• Which of the following symptoms would NOT be consistent with a manic episode?
A. Racing thoughts
B. Excessive speech
C. Hypersomnia
D. Impulsiveness
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Question #2
• Most patients with bipolar disorder experience:
A. Comorbid substance use or anxiety
B. The rapid cycling form of the illness
C. Initial mood episodes in their 40s
D. Manic episodes only
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Pharmacotherapy Options
• Lithium
• Anticonvulsants
– Valproate
– Carbamazepine
– Lamotrigine
• Second generation antipsychotics
• Others – FGAs, BZDs, other anticonvulsants, antidepressants
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Antimanic
Antidepressant
Prevention
of mania
Prevention
of depression
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FDA-Approved DrugsDrug Mania Depression Maintenance
Lithium √ √
Valproate √
Carbamazepine √
Lamotrigine √
Aripiprazole √ √
Asenapine √
Cariprazine √
Lurasidone √
Olanzapine √ √
Olanz/fluoxetine √
Quetiapine √ √ √
Risperidone √ √
Ziprasidone √ √
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Lithium
• Efficacy
– Very good antimanic, antidepressant, and maintenance effects; prevention of mania > depression
– Associated with lower rates of suicide
– Slower onset of action relative to VPA and SGAs (approx. 7-10 days in mania)
– Less effective for patients with mixed features or rapid cycling
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Lithium
• Adverse effects
– Renal: polyuria, chronic kidney effects
– CNS: tremor
– GI: N/V/D
– Endocrine/metabolic: weight gain, hypothyroidism, hyperparathyroidism
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Lithium
• Adverse effects (cont.)
– Cardiovascular: AV block/other conduction issues
– Hematologic: leukocytosis (benign)
– Dermatologic: acne, psoriasis, alopecia
– Reproductive/pregnancy: teratogenicity
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Lithium
• Toxicity
– Lithium has a narrow therapeutic index
– Signs and symptoms include coarse tremor, diarrhea, vomiting, and CNS symptoms such as confusion, dysarthria, and ataxia
– Can be life-threatening
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Lithium
• Drug interactions
– NSAIDS, COX-2 inhibitors (↑ Li level)
– Distal tubule diuretics (↑ Li level)
– ACE inhibitors, ARBs (↑ Li level)
• Dosing
– Initial dose: 300 mg bid or tid
– Usual dose: 900-1,800 mg/day
– Level: 0.6-1.2 mEq/L
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Lithium
• Safety monitoring
– Serum level
– CBC
– Electrolytes
– Calcium
– Creatinine/BUN
– TSH
– Weight/BMI
– As clinically indicated: ECG, pregnancy
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Valproate
• Efficacy
– Indicated for mania, but good maintenance medication as well
– Very good antimanic effects and some antidepressant effects; prevention of mania > depression
– Effective in combination with lithium or SGAs
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Valproate
• Adverse effects
– GI: N/V/D, pancreatitis
– Hepatic: elevated LFTs, hepatotoxicity
– CNS: sedation, tremor, ataxia
– Endocrine/metabolic: weight gain, hyperammonemia
– Hematologic: thrombocytopenia
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Valproate
• Adverse effects (cont.)
– Dermatologic: alopecia, rash
– Reproductive/pregnancy: menstrual irregularities, teratogenicity
• Drug interactions
– Lamotrigine (↑ lamotrigine level)
– Carbamazepine (↑ CBZ-epoxide levels; ↓ VPA levels)
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Valproate
• Dosing
– Initial dose: 250 mg bid or tid OR load with 20 mg/kg/day OR load with 30 mg/kg/day x 2 days, then decrease dose to 20 mg/kg/day
– Usual dose: 1,000-1,500 mg/day
– Max dose: 60 mg/kg/day
– Level: 50-125 mcg/mL
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Valproate
• Safety monitoring
– Serum level
– CBC
– LFTs
– Weight/BMI
– As clinically indicated: menstrual history, pregnancy, ammonia level
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Carbamazepine
• Efficacy
– Indicated for mania
– Good antimanic effects and some antidepressant effects; prevention of mania > depression
– Not as commonly used as other mood stabilizers; usually reserved for patients who don’t tolerate or fail to respond to other mood stabilizers
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Carbamazepine
• Adverse effects
– CNS: dizziness, sedation, diplopia, ataxia, tremor
– GI: nausea, vomiting, constipation
– Hematologic: thrombocytopenia, neutropenia, agranulocytosis, aplastic anemia
– Dermatologic: pruritus, rash, SJS/TEN
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Carbamazepine
• Adverse effects (cont.)
– Endocrine/metabolic: hyponatremia, weight gain
– Hepatic: elevated LFTs, hepatotoxicity
– Reproductive/pregnancy: teratogenicity
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Carbamazepine
Drugs ↑ CBZ levels
• Valproate
• Fluoxetine
• Cimetidine
• Erythromycin
• Ketoconazole
• Verapamil, diltiazem
CBZ ↓ levels of drugs
• Valproate
• Lamotrigine
• Antidepressants
• Antipsychotics
• Benzodiazepines
• Oral contraceptives
• Warfarin
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Carbamazepine
• Dosing
– Initial dose: 100-200 mg bid
– Usual dose: 600-1,200 mg/day
– Level: 4-12 mcg/mL (but no clear correlation with efficacy in bipolar disorder)
– Adjustments may be necessary due to autoinduction
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Carbamazepine
• Safety monitoring
– Serum level
– CBC
– Electrolytes
– LFTs
– Rash
– As clinically indicated: pregnancy, HLA-B*1502
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Lamotrigine
• Efficacy
– Indicated for maintenance treatment but used in acute depression as well
– Good antidepressant effects, but no real antimanic effects; maintenance effects are more impressive, but prevention of depression > mania
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Lamotrigine
• Adverse effects
– Dermatologic: rash, SJS/TEN
– GI: N/V/D
– CNS: dizziness, headache, sedation, diplopia, ataxia
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Lamotrigine
• Drug interactions
– Valproate (↑ lamotrigine level)
– Carbamazepine (↓ lamotrigine level)
– Estrogen-containing products (↓ lamotrigine level)
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Lamotrigine
• Dosing
– Usual titration: 25 mg/day for 2 weeks, then 50 mg/day for 2 weeks, then 100 mg/day for 1 week, then 200 mg/day
– Dosage adjustments: reduced dosages (approx. one-half) when given with valproate, and increased dosages (approx. double) when given with carbamazepine
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Lamotrigine
• Safety monitoring
– Rash
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SGAs
• Efficacy
– Various SGAs are FDA-approved for mania, depression, and maintenance (with or without Li or VPA)
– SGAs vary in regard to efficacy in the various phases
• Quetiapine – very good antimanic, antidepressant, and maintenance effects
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SGAs
• Efficacy (cont.)• Aripiprazole, Risperidone, Ziprasidone –
very good antimanic effects and very good at preventing mania; not useful for depression
• Lurasidone – very good antidepressant effects; limited maintenance effects
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SGAs
• Adverse effects
– CNS: sedation, EPS
– Endocrine/metabolic: weight gain, hyperglycemia, dyslipidemia, hyperprolactinemia
– Cardiovascular: decreased blood pressure, tachycardia, QT prolongation
– GI: dry mouth, constipation
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SGAs
• Drug interactions
– Various pharmacodynamic interactions
– Most SGAs are CYP450 substrates, so metabolism can be influenced by various inducers and inhibitors
• Ex: olanzapine levels can be decreased by carbamazepine
• Ex: risperidone levels can be increased by fluoxetine
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SGAsSGA Initial dose Usual dose
Aripiprazole 15 mg/day 15-30 mg/day
Asenapine 10 mg bid 5-10 mg bid
Cariprazine 1.5 mg/day 3-6 mg/day
Lurasidone 20 mg/day 20-120 mg/day
Olanzapine 10-15 mg/day 5-20 mg/day
Quetiapine
(mania)
50 mg bid or 300 mg qhs (XR)
400-800 mg/day
given bid or hs (XR)
Quetiapine
(dep)
50 mg qhs 300 mg qhs
Risperidone 2-3 mg/day 1-6 mg/day
Ziprasidone 40 mg bid 40-80 mg bid
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SGAs
• Safety monitoring
– Weight/BMI
– Waist circumference
– Blood pressure
– Fasting glucose
– Fasting lipids
– Extrapyramidal side effects
– As clinically indicated: ECG, prolactin
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Other Medications
• First generation antipsychotics
– Considered effective antimanic agents
– Lack efficacy in maintenance treatment and may cause switch to depression
– Not used nearly as much as SGAs
• Benzodiazepines
– Adjunctive treatment in mania
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Other Medications
• Other anticonvulsants
– Oxcarbazepine: limited data supporting use in mania; some adv./disadv. relative to CBZ
– Tiagabine, topiramate, zonisamide, gabapentin, levetiracetam: not recommended
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Other Medications
• Antidepressants
– Use is highly controversial
– Antidepressants can cause mood switching and perhaps accelerate episode frequency or induce rapid cycling
– As concerns drug classes, SNRIs and TCAs are most likely to cause mood switching
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Other Medications
• Antidepressants (cont.)
– Monotherapy should be avoided
– Adjunctive therapy can be used:
• Acute depression when there is a history of previous positive response
• Maintenance treatment if depressive episodes occur after stopping antidepressants
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Other Medications
• Antidepressants (cont.)
– Adjunctive therapy should be avoided:
• Manic or mixed states
• Past history of mood switching during antidepressant treatment
• High mood instability or rapid cycling
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Question #3
• Which of the following OTC products is MOST likely to cause lithium toxicity if used concomitantly?
A. Tagamet HB
B. Imodium
C. Zyrtec
D. Aleve
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Question #4
• Routine long-term safety monitoring of olanzapine use in bipolar disorder would include which of the following?
A. Liver function test
B. Prolactin level
C. Fasting glucose
D. Thyroid stimulating hormone
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Phases of Treatment
• Acute
– Resolve current mood episode
– Typical time frame for treatment response
• Mania: within approx. 2 weeks
• Depression: within approx. 4 weeks
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Phases of Treatment
• Continuation
– Prevent relapse or polarity switch
– Approx. 3 months
• Maintenance
– Prevent future mood episodes
– Lifetime
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Treatment Guidelines
Guideline Year
World Federation of Societies of Biological Psychiatry (WFSBP)
2009 (mania), 2010 (bipolar depression), 2012 (maintenance)
Canadian Network for Mood and Anxiety Treatments (CANMAT) & International Society for Bipolar Disorders (ISBD)
2013
National Institute for Health and Care Excellence (NICE)
2014
British Association for Psychopharmacology (BAP)
2016
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Treatment Guidelines –Mania
WFSBP CANMAT
1 Aripiprazole, Risperidone, Ziprasidone, VPA
Monotherapy: Li, VPA, Aripiprazole, Asenapine, Olanzapine, Paliperidone, Quetiapine, Risperidone, ZiprasidoneAdjunctive therapy: Li or VPA + Aripiprazole, Asenapine, Olanzapine, Quetiapine, Risperidone
2 Switch to another 1st choice medication; consider combination in severe mania
Monotherapy: CBZ, haloperidolCombination therapy: Li + VPA
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Treatment Guidelines –Mania
WFSBP CANMAT
3 Combination treatment with 2 1st choice medications
Various options including Chlorpromazine, Clozapine, Oxcarbazepine, others
4 Exchange one medication in step above with Li, CBZ, Haloperidol, Olanzapine, Quetiapine, others
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Treatment Guidelines –Mania
NICE BAP
1 If not taking mood stabilizer: Haloperidol, Olanzapine, Quetiapine, RisperidoneIf taking Li or VPA: optimize treatment, then if insufficiently effective, consider adding one of the 1st line medications above
Highest efficacy: Haloperidol, Olanzapine, Quetiapine, RisperidoneAlternatives: Li, VPA, CBZ
2 Switch to another 1st line medication
1st line medication + Li or VPA
3 1st line medication + Li or VPA (if Li is ineffective or unsuitable)
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Treatment of Mania
• General conclusions from guidelines
– 1st-line options: Li, VPA, and SGAs
– 2nd- or 3rd-line options: CBZ, FGAs
– Treatment-resistance: ECT, clozapine
• Combination therapy
– Li or VPA + SGA
– More effective than monotherapy
– Especially in severe/psychotic cases
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Treatment of Mania
• Antidepressants should be tapered and discontinued when possible
• Benzodiazepines can be used as short-term adjunctive treatment for anxiety, agitation, and insomnia
• Presence of mixed features
– Predictor of non-response to Li
– Should avoid antidepressants
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Treatment Guidelines –Depression
WFSBP CANMAT
1 Quetiapine, Olanzapine, Lamotrigine, Li, VPA, CBZ
Monotherapy: Li, Lamotrigine, Quetiapine Combination therapy: Li or VPA + SSRI or Bupropion, Olanzapine + SSRI, Li + VPA
2 Switch to or combine with another recommended medication
Monotherapy: VPA, LurasidoneCombination therapy: Li or VPA + Lamotrigine or Lurasidone, Quetiapine + SSRI
3 Consider various augmentation treatments, including antidepressants, modafinil, N-acetylcysteine, others
Various options including CBZ, Olanzapine, and numerous combinations
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Treatment Guidelines –Depression
NICE BAP
1 If not taking mood stabilizer: Olanzapine/Fluoxetine, Quetiapine, Olanzapine (alone), LamotrigineIf taking Li or VPA: optimize treatment, then if insufficiently effective, add one of the 1st
line medications above
Lurasidone, Olanzapine, Quetiapine, Lamotrigine
2 Switch to LamotrigineLamotrigine + Li or VPA
Switch to another 1st line medication or combine 2 1st
line medicationsConsider antidepressant + antimanic drug
3
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Treatment of Depression
• General conclusions from guidelines
– 1st-line options: Li, lamotrigine, quetiapine, lurasidone, olanzapine/fluoxetine (latter 3 are FDA-approved)
– 2nd- or 3rd-line options: Antidepressants (along with mood stabilizer), VPA, CBZ
– Treatment-resistance: ECT
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Treatment of Depression
• Combination therapy
– Two 1st-line medications
– Especially after failed monotherapy
• APDs are recommended in psychotic cases
• Negative results with some SGAs (aripiprazole, ziprasidone)
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Treatment Guidelines –Maintenance
WFSBP CANMAT
1 Aripiprazole, Quetiapine, Lamotrigine, Lithium
Monotherapy: Li, Lamotrigine, VPA, Aripiprazole, Olanzapine, Quetiapine, Risperidone LAIAdjunctive therapy: Li or VPA + Aripiprazole, Quetiapine, Risperidone LAI, or Ziprasidone
2 Olanzapine, Risperidone Monotherapy: CBZ, PaliperidoneCombination therapy: Li + VPA, CBZ, Lamotrigine, or Risperidone, Li or VPA + Olanzapine, Olanzapine + Fluoxetine
3 Paliperidone, Ziprasidone, Antidepressants, VPA
Various options
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Treatment Guidelines –Maintenance
NICE BAP
1 Li Li
2 If poorly tolerated or unsuitable: Olanzapine, Quetiapine, VPAIf ineffective: Li + VPA
If poorly tolerated or unsuitable: VPA or APDIf ineffective:Depression predominant? Li + Lamotrigine, Quetiapine, or LurasidoneMania predominant? Li + VPA or APD
3
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Maintenance Treatment
• General conclusions from guidelines
– 1st-line options: Li, lamotrigine, VPA, SGAs (aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone)
• Combination treatment
– Li or VPA + SGA, Li + VPA
– But monotherapy is ideal
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Maintenance Treatment
• Medication selection
– Influenced by patient’s illness pattern
– Medications are different in their ability to prevent manic and depressive episodes
• SGAs have safety concerns in long-term use
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Treatment Goals
• Resolve mood episodes
• Prevent future mood episodes
• Normalize functioning
• Minimize adverse effects
• Maximize medication adherence
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Evaluation of Therapeutic Outcomes
• Mood charting
• Functional status
• Suicidality
• Frequency/severity of symptoms
• Formal rating scales (examples)
– Mania: Young Mania Rating Scale
– Depression: Hamilton Depression Rating Scale
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Question #5
• Which of the following would be the BEST option after a trial of risperidone for treatment of acute mania is insufficiently efficacious?
A. Add ziprasidone
B. Add valproate
C. Switch to lorazepam
D. Switch to clozapine
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Question #6
• All of the following would be good options for long-term maintenance treatment of bipolar disorder EXCEPT:
A. Fluoxetine
B. Lamotrigine
C. Lithium
D. Quetiapine
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Q&A
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References
• Treatment guidelines
– WFSBP: World Journal of Biological Psychiatry
• Mania: 2009;10(2):85-116.
• Depression: 2010;11:81-109.
• Maintenance: 2013;14:154-219.
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References
– CANMAT/ISBD: Bipolar Disorders 2013;15(1):1-44.
– NICE: nice.org.uk/guidance/cg185
– BAP: Journal of Psychopharmacology 2016;30(6):495-553.
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References
• Other guidelines
– ISBD Task Force re: antidepressant use in bipolar disorders: American Journal of Psychiatry 2013;170(11):1249-1262.
– ISBD consensus re: safety monitoring of bipolar disorder treatments: Bipolar Disorders 2009;11:559-595.
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References
• Books/chapters
– DSM-5: Diagnostic and Statistical Manual of Mental Disorders, 5th ed.
– Drayton SJ, Fields CS. Bipolar disorder chapter of Pharmacotherapy: A Pathophysiologic Approach, 10th ed.
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References
– Ott C. Bipolar disorder chapter of 2018-2019 CPNP BCPP Examination Review and Certification Course
– Kehoe WA. Psychiatric disorders chapter of ACCP Updates in Therapeutics 2017