CHALLENGES IN THE MANAGEMENT OF BIPOLAR DISORDER Learning - - PowerPoint PPT Presentation

CHALLENGES IN THE MANAGEMENT OF BIPOLAR DISORDER

Learning Objectives

• Implement evidence-based treatment for

patients with bipolar disorder

• Address common clinical challenges in the

treatment of bipolar disorder

More Specifically, When We’re Done, You Will Know…

How to recognize and use moderators and mediators of treatment outcome to tailor individualized pharmacotherapy How to implement evidence-based pharmacotherapy in routine clinical practice When to use or not use antidepressants in bipolar disorder How to differentiate among antidepressant properties of second generation antipsychotics When to discontinue antipsychotics after an index episode How to recognize niche roles for specific mood stabilizers How to manage common psychiatric comorbidities in bipolar disorder How to manage common adverse effects of medications for bipolar disorder

ALL IN UNDER 90 MINUTES!

Matching: Brokering the Best Fit

Clinical Domains Moderators and Mediators Medications Mania Age Lithium Depression Sex Divalproex Mixed features Race Carbamazepine Psychosis Age at onset Lamotrigine Rapid cycling Familiality Topiramate Attentional problems Pharmacogenetics Gabapentin Anxiety Baseline severity Monoaminergic antidepressants Alcohol/substance use disorders Polarity proneness OFC, QUET, LURAS, CARIP Impulsive aggression Episode number Other SGAs Affective instability Chronicity Stimulants Overweight/metabolic dysregulation Past treatment response Hormones (e.g., T4) Insomnia Psychosocial stressors Calcium channel blockers Suicidality BP I vs. BP II Ketamine

Matching: Brokering the Best Fit

Clinical Domains Moderators and Mediators Medications Mania Age Lithium Depression Sex Divalproex Mixed features Race Carbamazepine Psychosis Age at onset Lamotrigine Rapid cycling Familiality Topiramate Attentional problems Pharmacogenetics Gabapentin Anxiety Baseline severity Monoaminergic antidepressants Alcohol/substance use disorders Polarity proneness OFC, QUET, LURAS, CARIP Impulsive aggression Episode number Other SGAs Affective instability Chronicity Stimulants Overweight/metabolic dysregulation Past treatment response Hormones (e.g., T4) Insomnia Psychosocial stressors Calcium channel blockers Suicidality BP I vs BP II Ketamine

OFC: olanzapine-fluoxetine combo; QUET: quetiapine; LURAS: lurasidone; CARIP: cariprazine

Moderators: (“who should get the treatment”) Baseline characteristics that influence outcome:

• Age at onset
• Baseline severity
• Chronicity
• Episode number
• Polarity proneness
• Sex
• Rapid cycling
• Comorbidities
• Hx of childhood trauma
• Familiality
• Poor metabolizer genotype

Mediators: (“how to get the best treatment

• utcomes”)

Factors that influence treatment outcome after treatment has begun

• Treatment adherence
• Drug-drug interactions
• Therapeutic alliance
• Stressful life events after treatment has begun
• Adverse drug effects or nocebo effects

Am J Psychiatry 2016;173:672-9.

"Ignored moderators may be one explanation for why so many psychiatric treatments appear to have such low effectiveness." (Kraemer, 2016)

Moderators and Mediators of Outcomes in Clinical Trials

Moderators: (“who should get the treatment”) Baseline characteristics that influence outcome:

• Age at onset
• Baseline severity
• Chronicity
• Episode number
• Polarity proneness
• Sex
• Rapid cycling
• Comorbidities
• Hx of childhood trauma
• Familiality
• Poor metabolizer genotype

Mediators: (“how to get the best treatment

• utcomes”)

Factors that influence treatment outcome after treatment has begun

• Treatment adherence
• Drug-drug interactions
• Therapeutic alliance
• Stressful life events after treatment has

begun

• Adverse drug effects or nocebo effects

Kraemer et al. Am J Psychiatry 2016;173:672-9.

"It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has” (Sir William Osler)

Mood Stabilization: Above vs. Below Baseline

Ketter, Calabrese. J Clin Psychiatry 2002;63:146-51.

Why Isn’t Lamotrigine FDA-Approved for Bipolar Depression?

Or: Why Baseline Severity is a Critical Outcome Moderator

Moderate Baseline Severity High Baseline severity Lamotrigine Response Rate 48% 45% Placebo Response Rate 45% 30%

Geddes et al. Br J Psychiatry 2009;194:4-9.

LAMLIT: Lamotrigine+Lithium

Challenge: High Placebo Response Rates and Failed Trials

Bipolar Mania:

• Low baseline severity1
• Absence of psychosis2
• Women1
• Older age1

Bipolar Depression:

• Low baseline severity3
• Longer duration of

treatment3

Other clinical correlates of placebo responsivity: dispositional optimism; external locus of control; novelty-seeking; neuroticism; favorable expectancy4

1 Yildiz et al. Int J Neuropsychopharmacol 2011;14:863-75; 2 Welten et al. Eur Neuropsychopharmacol 2015;25:1018-26; 3 Nierenberg et al. Int Clin Psychopharmacol 2015;30:59-66; 4 Goldberg & Stahl. Practical Psychopharmacology.

Cambridge Univ Press, in press.

Pooled response rate =31% (95% CI=28-33%)1

The Damn Placebo Effect: N-Acetylcysteine in Bipolar Depression

Ellegaard et al. J Affect Disord 2019;245:1043-51.

20-week RCT of NAC (3 gms/day; N=80) or placebo (n=80) No significant difference in MADRS scores by mixed regression Placebo response rate=55.6%

More on Moderators: Episode Number and Antimanic Response

Swann et al. Am J Psychiatry 1999;156:1264-6.

More on Outcome Moderators: Polarity Proneness

Popovic et al. Eur Neuropsychopharmacol 2012;22:339-46.

NNT: Number needed to treat

Antidepressants: Class Effect? All Bad? Some Good?

Sachs et al. N Engl J Med 2007;356:1711-22.

Don’t Use Antidepressants in Bipolar Depression with Mixed Features

Interaction Effect: Antidepressant use x # of mania symptoms at baseline = higher YMRS score after 3 months (p=.003) Stanley Bipolar Network: antidepressants exacerbate mania when low-grade baseline mania symptoms are present 355 STEP-BD entrants with major depression with >1 manic symptoms Goldberg et al. Am J Psychiatry 2007;164:1348-55. Frye et al. Am J Psychiatry 2009;166:164-72.

When to Use or Not Use Antidepressants:

Sustained Improvement Only if Robust Acute Response

OR (1-year response: 5.89, p<.001)

Altshuler et al., J Clin Psychiatry 2009; 70: 450-457

35% 13% 9%

69% 13% 27% 23%

Antidepressants in BP II Depression

But: the results pertain to initial fluoxetine responders

• 148 received open label fluoxetine

monotherapy for 12 weeks

• 49.7% recovered and were then

randomized to fluoxetine (mean dose 34 mg/day) vs. lithium (mean dose 1027 mg/day, mean serum [Li+]=0.69 mEq/L vs placebo

Wow— fluoxetine looks even better than lithium!

Amsterdam & Shults. Am J Psychiatry 2010;167:791-800.

Fluoxetine monotherapy for relapse prevention in bipolar II depression

Antidepressants in BP II Depression

Comparable response rates over study period

No difference in switch rates: Lithium=14%; Sertraline=17%; Both=10%

Altshuler et al. Am J Psychiatry 2017;174:266-76.

Can Pharmacogenomics Help Gauge Risk for Antidepressant- Induced Mania?

Serotonin Transporter Gene (SLC6A4) and Risk for Antidepressant-Induced Mania

“s” allele: RR=1.35 (95% CI=1.04-1.76, p=.02)

Daray et al. Bipolar Disord 2010;12:702-6.

When to Use or Not Use Antidepressants in Bipolar Depression

Favors Antidepressant Use Discourages Antidepressant Use BP II BP I Pure depressed episodes Mixed features Absence of rapid cycling Past year rapid cycling Absence of recent mania/hypomania Mania/hypomania in past 2–3 months Absence of comorbid alcohol/substance use disorders Alcohol or substance use comorbidity Prior favorable antidepressant response Suboptimal responses to prior antidepressants No history of antidepressant- induced mania History of antidepressant-induced mania/ hypomania

Goldberg & Stahl. Practical Psychopharmacology, Cambridge Univ Press 2020.

Randomized Trials of D2/D3 Partial Agonists in Bipolar Depression

Agent D3 Ki RCTs in Bipolar Depression Aripiprazole 0.8-9.7 nM Acute: Two (-) acute RCTs;1 Maintenance: 1 (-) RCT (oral monotherapy),2 1 (-) RCT (LAI)3 Brexpiprazole 1.1 nM Acute: One small (n=21) 8-week open label flexibly-dosed (mean=2.78 mg/day) trial; significant improvement from baseline depression scores (d=1.4), 73.6% were “responders”4 Maintenance: no data Cariprazine 0.085 nM Acute: 2 (+) 8-week FDA registration RCTs in acute bipolar depression:

• ITT n=571: 1.5 mg/day (but not 0.75 or 3 mg/day) > placebo5
• ITT n=480: 1.5 mg/day or 3 mg/day > placebo6

Maintenance: no data

1 Thase et al. J Clin Psychopharmacol 2008;28:13-20; 2 Keck et al. J Clin Psychiatry 2007;68:1480-91; 3 Calabrese et al.

J Clin Psychiatry 2017;78:324-31; 4 Brown et al. J Affect Disord 2019;249:315-8; 5 Durgam et al. Am J Psychiatry 2016;173:271-81; 6 Earley et al. Am J Psychiatry 2019;176:439-48.

Aripiprazole in Bipolar Depression: Failed or Negative Trial?

Thase et al. J Clin Psychiatry 2008;28:13-20.

Randomized Trials of D2 Pure Antagonists in Bipolar Depression: Positive Data

Agent RCTs in Bipolar Depression Asenapine (Acute: No data) Maintenance: 26-week RCT: better prevention of depression (as well as mania) than with placebo1 Lurasidone Acute: 1 (+) monotherapy,2 1 (+) augmentation (lithium/divalproex)3 RCT Olanzapine Acute: 2 (+) monotherapy RCTs,4 1 (+) augmentation (w/fluoxetine),5 Maintenance: 1 (+) 18-month RCT: better prevention of depression (as well as mania) than with placebo6 Quetiapine Acute: 9 (+) adult RCTs7 Maintenance: 1 (+) RCT: better prevention of depression (as well as mania) than with placebo8

1 Szegedi et al. Am J Psychiatry 2018;175:71-79; 2 Loebel et al. Am J Psychiatry 2014;171:160-8; 3 Loebel et al. Am J

Psychiatry 2014;171:169-77; 4 Tohen et al. J Affect Disord 2013;149(1-3):196-201; 5 Tohen et al. Arch Gen Psychiatry 2003;60:1079-88; 6 Tohen et al. Am J Psychiatry 2006;163:247-56; 7 Suttajit et al. Drug Des Devel Ther 2014;8:827-38;

8 Weisler et al. J Clin Psychiatry 2011;72:1452-64.

Randomized Trials of D2 Pure Antagonists in Bipolar Depression: Negative Data

Agent RCTs in Bipolar Depression Lurasidone Maintenance: 1 (-) RCT (adjunct to lithium or divalproex)1 Risperidone (Acute: No data) Maintenance: 1 (+) RCT2 Ziprasidone Acute: 2 (-) RCTs 3 Maintenance: 1 (-) RCT4

1 Calabrese et al. Eur Neuropsychopharmacol 2017;27:865-76; 2 Quiroz et al. Biol Psychiatry 2010;68:156-62; 3 Sachs et

• al. J Clin Psychiatry 2011;72:1413-22; 4 Bowden et al. J Clin Psychiatry 2010;71:130-7.

Lumateperone in Bipolar Depression

Durgam et al. ACNP Ann Meeting 2019.

When to Stop a Second-Generation Antipsychotic After Acute Response in Mania

N=159 BP I manic patients treated with Li+ or DVPx plus olanzapine or risperidone After 24 weeks: Relapse Hazard Ratio: Overall=0.53 (95% CI=0.33-0.86) RIS=1.85 (95% CI=1.00-3.41) OLZ=0.48 (95% CI=0.17-1.32)

Yatham LN et al. Mol Psychiatry 2016;21:1050-6.

The magic number is…

Ketamine in Bipolar Depression

Parsaik et al. J Psychiatr Pract 2018;21:427-35.

Pramipexole and Bipolar Depression: D3 Strikes Again

Open case series of high-dose (up to 5 mg/day; mean dose=2.5 mg/day) pramipexole in 18 BP depressed patients with >4 prior antidepressant nonresponses: Response or remission= 14/18=78% Agitation/activation= 1/18 = 6%

Fawcett et al. Am J Psychiatry 2016;173:107-11.

(Ar)modafinil in Bipolar Depression

Five randomized controlled trials in bipolar depression (three positive, two negative): greater rates of response (RR=1.18, 95% CI=1.01-1.37, p-=0.03)

• r remission (RR=1.38, 95% CI=1.10-1.73, p=.005)

NNT=16

Nunez et al. Bipolar Disord 2019;Oct 23:doi:10.1111/bdi.12859.

Rapid Cycling

• Li+ + DVPX: only 24% of RC patients

(n=254) stabilized on open-label lithium + divalproex, and half of those remained stable when randomized to either monotherapy1

Relapse into Mania or Depression

• Triple mood stabilizers:2

LTG 150-200 mg/day x 12 weeks 10 20 30 40 50 60 70 Li (n=32) DVPX (n=28)

1 Calabrese et al. Am J Psychiatry 2005;162:2152-61; 2 Kemp et al. Bipolar Disord 2012;14:780-9.

Treatment of Anxiety Symptoms During Mania: Divalproex

8-week comparison of DVPX (N=13) or PBO (N=12) ES=1.05 Mean [VPA]=80 ng/dL

Davis et al. J Affect Disord 2005;85:259-66.

6-week comparison of DVPX or PBO Mean [VPA]=70 ng/dL

Ghaemi et al. J Clin Psychiatry 2007;68:1840-4. Mean ∆ HAM-Anxiety Scale

p<0.0001

Mean ∆ HAM-Anxiety Scale

Suicide Prevention: Lithium vs. Divalproex

Oquendo et al. Am J Psychiatry 2011;168:1050-6.

Suicide Prevention: Lithium vs. Divalproex

Nonrandomized observational data

Goodwin et al. JAMA 2003;290:1467-73.

Comorbidities: Anxiety in Bipolar Disorder

Δ in HAM-A Score From Baseline

Olanzapine-Fluoxetine Combination1

Δ in HAM-A Score From Baseline

Quetiapine2

1 Tohen et al. Arch Gen Psychiatry 2003;60:1079-88; 2 Hirschfeld et al. J Clin Psychiatry 2006;67:355-62.

Comorbidities: Anxiety in Bipolar Disorder

Δ in HAM-A Score From Baseline

Lurasidone1

1 Loebel et al. Am J Psychiatry 2014;171:160-8; 2 Earley et al. Am J Psychiatry 2019;176:439-48.

Cariprazine2

Δ in HAM-A Score From Baseline

p=0.0144

Placebo Cariprazine 1.5 mg Cariprazine 3 mg

Symptom Domains: Treatment of Alcohol Use Comorbidity

PBO n=30 DVPX n=29 P Proportion of any drinking days 0.240 0.168 .080 Proportion of heavy drinking days 0.186 0.093 .021 Drinks/heavy drinking day 10.2 5.6 .018 Drinks/day 8.9 5.1 .022 Bech-Rafaelson Mania Scale 6.1 5.6 .87 HAM-D 14.4 16.3 .360

Salloum et al. Arch Gen Psychiatry 2005;62:37-45.

Divalproex vs. Treatment As Usual

Bipolar Disorder With Adult ADHD

Week

Baseline 1 2 3 4

Change in Mood Symptoms Change in ADHD Symptoms P<0.001 ES=0.76 P=0.035 ES=0.26 P<0.001 ES=0.74

Baseline 1 2 3 4

Week McIntyre et al. Hum Psychopharmacol 2013;28:421-7.

MADRS = Montgomery Asberg Depression Rating Scale; YMRS = Young Mania Rating Scale; CAARS = Conners' Adult ADHD Rating Scale; ADHD-RS = ADHD Rating Scale.

Safety of Lisdexamfetamine in Bipolar Depression

• 8-week randomized comparison of lisdexamfetamine (N=11) or placebo

(N=14) added to mood stabilizers/atypical antipsychotics

• Significant improvement in depressive subjective symptoms (IDS-SR)

(p=.04; ES=1.05) but not objective symptoms (MADRS)

• Significant improvement in binge eating (p=.03; ES=0.79) and daytime

fatigue (p<.01; ES=1.18)

• No worsening of mania symptoms with LIS vs. placebo from baseline

(YMRS=4.3)

McElroy et al. Int Clin Psychopharmacol 2014;30:6-13.

Non-Mood Stabilizer Anticonvulsants

GAD Social Anxiety* Neuro- pathic Pain Migraine Insomnia* RLS Weight Loss/Binge Eating Alcohol Use Disorder Gabapentin √ √ √ √ √ √ Pregabalin √ √ √ Topiramate √ √ √ Zonisamide √ Levetiracetam ?

Goldberg & Stahl. Practical Psychopharmacology, Cambridge Univ Press 2020.

* Off-label use

Addressing Cognitive Complaints

• Minimize anticholinergics (e.g., amantadine > benztropine for EPS)
• Withania somnifera 250-500 mg/day > placebo for short-term

memory (digit span backward; ES=0.51), reaction time, social cognition1

• Creatine monohydrate 6000 mg/day x 6 weeks: Better verbal

fluency2

• Pramipexole: Better attentional processing (digit span) and

executive function (Stroop color) in euthymic bipolar patients3

• Lurasidone > treatment as usual for improving global cognition

(mean difference =2.92 [95% CI 0.27–5.57], p=0.032.; ES= 0.82)4

1 Chengappa et al. J Clin Psychiatry 2013;74:1076-83; 2 Toniolo et al. J Affect Disord 2017;224:69-75; 3 Burdick et al. J Clin Psychiatry 2012;73:103-12; 4 Yatham et al. Lancet Psychiatry 2017;4:208-17.

Clinical Profiling: When to Use Lithium

• First (few) episode(s)1
• + family history of lithium responsivity (67% concordance)2
• Mania-prone > depression prone
• Pure euphoric > mixed features
• Absence of rapid cycling
• Absence of comorbid substance use disorders
• History of suicide attempt (though divalproex may be

noninferior)

1 Gelenberg et al. N Engl J Med 1989;321:1489-93; 2 Grof et al. J Clin Psychiatry 2002;63:942-7.

Clinical Profiling: When to Use Divalproex in Bipolar Disorder

• Multi-episode presentations
• Mania-prone > depression prone
• Mixed or pure manias
• Impulsivity/aggression
• Presence or absence of rapid cycling
• Presence or absence of comorbid alcohol/substance

use disorders

• Avoid in sexually active women of reproductive potential

Lithium + Divalproex in Bipolar Maintenance

BALANCE Investigators. Lancet 2010, Jan 30;375(9712):385-95.

330 BP I patients treated w/combination of lithium + divalproex then randomized to either monotherapy or the combination for 2 years 1o Outcome = Time to Intervention for an Emerging Mood Episode: Relapse: HR p Combo 54% 0.59 (combo vs. divalproex) 0.0023 Lithium alone 59% 0.71 (lithium vs. divalproex) 0.0472 Divalproex alone 69% 0.82 (combo vs. lithium) 0.27

• Relapse risk was independent of baseline severity

HR: Hazard ratio

Managing Mood Stabilizers: Lithium

Agent Main Concerns for End-Organ Monitoring Management Strategies Lithium Thyroid Semi-annual TSH; check antibodies if hypothyroid; treat with levothyroxine PTH 10–25% incidence of hyperCa++ w/elevated PTH; see hypercalcemia w/low urine Ca++; cinacalcet? Postural tremor Assure non-toxic serum level; propranolol 20–90 mg/day Renal function qHS dosing may diminish risk for CKD Urinary frequency/nephrogenic DI Amiloride 5 mg PO BID

Goldberg & Ernst. Managing the Side Effects of Psychotropic Medications, 2nd Ed., APA Press 2019.

Managing Mood Stabilizers: Anticonvulsants

Agent Main Concerns for End- Organ Monitoring Management Strategies Divalproex Hepatic monitoring; dose- related thrombocytopenia; tremor; GI upset Hy’s Law: LFTs <3x upper limit of normal + total bilirubin <2x normal; no other etiologies; asymptomatic hyperammonemia may be of no clinical significance if serum [NH3]<127 μg/dl) Carbamazepine Hepatic enzyme (auto)induction; rare aplastic anemia; cutaneous reactrions Benign leukopenia in ~1/3, 1st 6 months; aplastic anemia in 1/200,000 cases; HLA-B*1502 in SE Asians ■ Lamotrigine Cutaneous reactions; metabolism induced by estrogen Severe rashes most common in weeks 2-8; halve dosing/titration w/divalproex or patients <18 May need to increase dosing in pregnancy

Goldberg & Ernst, Managing the Side Effects of Psychotropic Medications, 2nd Ed., APA Press, 2019

Parsimonious Polypharmacy: Synergy and/or Simplification

• Bipolar II depression + obesity + smoker =
• Bipolar disorder + generalized anxiety + insomnia +

neuropathic pain=

• Bipolar disorder + migraine + alcohol use disorder +

binge eating = Bipolar depression + ADD + obesity = Relative weight neutrality and bipolar depression = Bupropion Adjunctive gabapentin Adjunctive topiramate Adjunctive lisdexamfetamine

lurasidone; cariprazine; lamotrigine; bupropion (+ naltrexone? – esp. w/alcohol misuse)

Take Home Messages

• Diagnosis alone is insufficient to devise an optimal pharmacotherapy regimen;

moderators and mediators are central to a bespoke treatment

• Characterize patients by bipolar subtype, comorbidities, polarity-proneness,

cycling frequency, psychosis

• Beware drawing causal inferences from nonrandomized/observational or

underpowered studies when applying evidence-based findings to an individual patient

• Possible emerging role for pharmacogenetic testing
• Use parsimonious combinations targeting multiple symptom domains based on

reasonable inferences from existing evidence base

Post-test Question 1

You have been asked to consult on a 34-year-old woman with bipolar II depression with no mixed features, unresponsive to prior lithium and divalproex trials. She reports prominent anxiety, has no substance use disorder, and is homozygous l/l at the SLC6A4 locus of the serotonin

• transporter. All of the following would be evidence-based pharmacotherapies

in this case except which one?

• 1. Sertraline
• 2. Lamotrigine
• 3. Lumateperone
• 4. Quetiapine
• 5. Pramipexole

Post-test Question 2

The resident you are supervising laments that “lithium is an old drug” and asks why anyone would still prescribe it nowadays. Resisting the urge to rebuke, you gently point out that lithium would be a preferred and evidence- based treatment option in all of the following settings except which one?

• 1. Manic episodes with pure/non-mixed manic episodes
• 2. Patients in their first few lifetime episodes
• 3. Bipolar patients with a rapid cycling course specifier
• 4. Patients with a family history of lithium-responsive bipolar disorder
• 5. As a maintenance adjunct to divalproex instead of divalproex alone