Section 5: Use of Antidepressants in Bipolar Disorder

1
Section 5 Use of Antidepressants in Bipolar
Disorder
2
Treatment of Bipolar Depression

• Fewer studies than for mania
• Limited approved treatments
• Antidepressants lack evidence and may cause mood
  destabilization

Ghaemi SN, et al. J Clin Psychiatry.
200162565-569. Ghaemi SN, et al. Am J
Psychiatry. 2004161163-165.Muzina DJ,
Calabrese JR. Int J Neuropsychopharmacol.
20036285-291.
3
Use of Antidepressants in Bipolar Disorder

• Bipolar disorder is associated with considerable
  depressive morbidity
• Risk-to-benefit ratio of antidepressants as
  adjuncts to mood stabilizers is an area of
  controversy and disagreement
• Antidepressants may increase risk of iatrogenic
  mania, mixed states, rapid cycling
• APA 2002 guidelines recommend conservative use of
  antidepressants
• Although evidence of their safety and efficacy is
  limited, antidepressants are commonly used in
  treatment of bipolar depression

Hirschfeld RM et al. Presented at 156th American
Psychiatric Association Annual Meeting May
17-22, 2003 San Francisco, CA. Goldberg JF, et
al. Bipolar Disord. 20035407-420. American
Psychiatric Association. Practice Guidelines for
the Treatment of Patients With Bipolar Disorder.
2nd ed. Washington, DC American Psychiatric
Publishing Group 2002.
4
Bipolar Depression and AntidepressantsGeneral
Clinical Guidelines and Risks

• Conservative approach to antidepressant use
• Risk of antidepressant induced mood-cycling in
  about 1530 of patients
• Mood stabilizers (lithium, lamotrigine) are
  effective in acute and prophylactic treatment of
  depression lithium is effective in suicide
  prevention
• Antidepressants should be reserved for severe
  cases of acute bipolar depression and not used
  routinely
• Cost/risk benefit ratio for antidepressant
  treatment of bipolar depression is unfavorable
• Antidepressants should be discontinued after
  recovery from depressive episode (mixed evidence
  for this recommendation)

• American Psychiatric Association. Practice
  Guidelines for the Treatment of Patients With
  Bipolar Disorder. 2nd ed. Washington, DC
  American Psychiatric Publishing Group 2002.
• Ghaemi SN, et al. Bipolar Disord. 20035421-433.
• Ghaemi SN, et al. Am J Psychiatry.
  2004161163-165.

5
No Antidepressant Advantage For Paroxetine or
Imipramine If Lithium Levels Are Therapeutic
N 15 15 14 7 10 7
60
P NS
P 0.05
50
40
Responders per Hamilton Criterion 7
Li PBO
30
Li PAR
Li IMI
20
10
Switch Rates LiPBO 2.3 LiIMI 7.7 LiPAR 0
0
Overall Efficacy
Li 0.8 mEq/L
PBO Placebo PAR Paroxetine IMI Imipramine
Nemeroff CB, et al. Am J Psychiatry.
2001158906-912.
6
Antidepressant Efficacy Stanley Network
N 32 42 37 15 22
22
68.8
71.0
62.5
55.3
With CGI 1 or 2
48.5
43.0
Leverich GS, et al. Am J Psychiatry.
2006163232-239.
7
Time Until Switch With Antidepressants Stanley
Bipolar Network
1.0
0.8
P 0.03
0.6
Cumulative Proportion Without a Switch
0.5
0.2
Patients with bipolar I disorder (N 115)
Patients with bipolar II disorder (N 44)
Censored
0.0
200
300
100
400
500
0
Time to Switch (days)
Leverich GS, et al. Am J Psychiatry.
2006163232-239.
8
Ratio of Threshold Switches to Subthreshold Brief
Hypomanias
4.0
More Threshold Than Subthreshold Phenomena
3.5
3.0
2.5
Ratio of Threshold Switches to Subthreshold Brief
Hypomanias
2.0
1.5
1.0
More Subthreshold Than Threshold Phenomena
Bupropion
0.5
Sertraline
Venlafaxine
0.0
Acute Antidepressant Trials (10 weeks)
Continuation Antidepressant Trials ( 1 year)
Leverich GS, et al. Am J Psychiatry.
2006163232-239.
9
Maintenance Antidepressants in Bipolar Disorder

• Maintenance antidepressants efficacy has not been
  established in bipolar disorder
• Increased cycling on antidepressants has been
  shown in three placebo-controlled studies
• When antidepressants are used in acute therapy,
  taper and discontinue them after recovery from
  depression
• Maintain antidepressants only in those who
  repeatedly relapse soon after discontinuation
  (about 20 of bipolar patients)

Ghaemi SN, et al. Bipolar Disord. 20035421-433.
10
TIMA 2005 Bipolar Acute Depression
Stage 1
OtherAntimanic
No Antimanic, Severe or Recent Mania
No Antimanic,No Severe or Recent Mania
Taking Li
(Increase Li to 0.8 mEq/L)
(continue)
Antimanic Lamotrigine
Lamotrigine

• Lamotrigine is a mood stabilizer not antimanic
• Lithium is an antimanic
• If history of recent or severe mania, add or
  optimize antimanic
• Otherwise, lamotrigine monotherapy may be
  appropriate

Suppes T, et al. J Clin Psychiatry.
200566870-886.
11
TIMA 2005 Bipolar Acute Depression
Partial Response or Nonresponse
Stage 2
Quetiapine or Olanzapine-Fluoxetine
Response
Partial Response or Nonresponse
CONT
Stage 3
Combination from Li, LTG, QTP, or OFC

• Designed to minimize cycle risk
• Note no anticonvulsant except LTG until Stage 4
• Overlap and taper
• Follow ADA guidelines regarding metabolic
  monitoring

Suppes T, et al. J Clin Psychiatry.
200566870-886.
12
TIMA 2005 Bipolar Acute Depression
Response
CONT
Partial Response Or Nonresponse
Li, LTG, QTP, OFC, VPA, or CBZ SSRI, BUP, or
VEN or ECT
Stage 4

• Combinations (OFC combinations 3 drugs)
• Lamotrigine should not be combined with AD
  without antimanic
• Includes VPA and CBZ at this point
• SSRIs include CTP, FLX, PRX, SRT, and FLV
• Some advocate the use of AD earlier but
  evidence is lacking
• Venlafaxine associated with more mania
  induction

BUP bupropion CBZ carbamazepine CTP
citalopram ECT electroconvulsive therapy Li
lithium LTG lamotrigine OFC
olanzapine-fluoxetine combination QTP
quetiapine SSRI selective serotonin reuptake
inhibitor VEN venlafaxine VPA
valproate Suppes T, et al. J Clin Psychiatry.
200566870-886.
13
Bipolar Depression and Antidepressants General
Guidelines and Risks

• Always use mood stabilizer in bipolar I patients,
  even while depressed
• Promptly wean the antidepressant if evidence of
  hypomania or mania emerges
• Antidepressants may trigger mania (mood
  destabilization) or accelerate mood cycle
• Up to 33 of patients with bipolar disorder may
  be susceptible to antidepressant-induced manias
• Possibly less efficacious in bipolar than
  unipolar depression
• Few standard antidepressants have been studied in
  bipolar depression

Dantzler A, Osser DN. Psychiatr Ann.
199929270-284. Frances AJ, et al. J Clin
Psychiatry. 199859(suppl 4)73-79. Goldberg JF,
Ernst CL. J Clin Psychiatry. 200263985-991. Gold
berg JF, Truman CJ. Bipolar Disord.
20035407-420. Möller HJ, et al. J Affect
Disord. 200167141-146.
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Complicated Bipolar Relapse
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Presentation

• 32-year-old female
• Brought to ER by police
• Family called 911 after altercation at
• home escalated

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History of Present Illness

• Sister tells ER doctor that patient has been
  getting more irritable for last 6 weeks
• Missed outpatient psychiatrist appointment 2
  weeks ago
• Spent disability check and couldn't afford to
  fill prescription
• Sister suspects patient has started abusing
  cocaine again

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Past Psychiatric History

• Diagnosed with bipolar disorder at age 21
• 5 prior hospitalizations (3 manic episodes, 2
  depressive episodes with suicidality)
• Sporadic outpatient attendance with partial
  medication
• compliance
• Responded to lithium, but patient discontinued
  due to
• tremor
• Responded to valproic acid, but patient
  discontinued
• due to weight gain
• Noncompliance associated with cocaine abuse

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Recent Psychiatric History

• More irritable
• Feels her sister is checking on her too much
• Feels she can make a new start and called
• CNN and NBC seeking audition as newscaster
• Poor sleep pattern

19
Past Medical History

• Hypertension
• Obesity (BMI 32)
• Gallstone surgery

20
Social and Family History

• Social History
• Cigarette smoker
• 2 DUIs
• On disability for bipolar disorder
• Family History
• Mother has bipolar disorder
• First cousin committed suicide
  
• Patient has longstanding difficulties in her
  family relationship
• Divorced twice
• 1 child has ADHD, 1 cousin with bipolar disorder

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Mental Status Examination

• Intoxicated and irritable in ER
• Angry with her sister, vague threats (she
  better
• watch out if she continues to be so pushy)
• Speech pressured
• Tells ER doctor she doesn't want to be
  hospitalized because she is setting up interview
  with CNN
• If she doesn't get the job, it will be over

22
Differential Diagnosis

• Bipolar disorder, manic relapse
• Polysubstance abuse

23
Laboratory Tests

• Urinary drug screen positive for cocaine,
  benzodiazepines
• Pregnancy test negative
• Glucose and triglycerides normal
• Cholesterol mildly elevated
• Liver function tests normal

24
Clinical Course

• Initially refuses admission and becomes
• belligerent in ER
• Calmed by intramuscular (IM) injection of
• antipsychotic
• Later on required a second IM injection and
  admitted to the hospital
• Still irritable, pressured in speech, and
  sleeping
• 3 hours a night
• Quetiapine started with gradual titration to
• 600 mg/day

25
Clinical Course (cont)

• Patient decided to try lithium monotherapy for
  outpatient care
• Becomes more agreeable and engaged in treatment
• Reluctantly agrees to aftercare substance abuse
  day program
• Says she'll take her medications but that "they
  better not make me fatter"
  

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Case Summary

• Female with dual diagnosis bipolar disorder I
• Cardiovascular/weight comorbidities
• Intermittent noncompliance and substance abuse
  underlie poor long-term course and heightened
  risk of injurious behavior
• Doctor's capacity to achieve persistent clinical
  stability strongly influenced by patient's
  perceived effectiveness (risk versus benefit
  appraisal) of medications

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Key Messages

• Therapeutic engagement is a critical first step
  to treatment adherence
• Careful assessment of
• Medical and psychiatric comorbidities in bipolar
  disorder
• Treatment options (agents, formulations) in
  managing acutely agitated bipolar patients
• Treatment goals (choice agents, risk-benefit
  appraisal) in stabilization of bipolar patients
• Treatment priorities, decisions, and transition
  to outpatient maintenance therapy

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The Bland Chef
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History

• 37-year-old single female, without children,
  employed as a chef at a local hotel
• Chief complaint Im depressed and wired
• Diminished interest in her work, which she
  previously was passionate about
• No suicidal ideation
• Hyperphagia, hypersomnia, racing thoughts, feels
  anxious and hyper, irritable with friends,
  severe premenstrual worsening
• Mood instability admixed with nonrefreshing
  sleep, led to previous diagnosis of major
  depression

30
History of Present Illness

• Current episode began approximately six months
  ago in the absence of identifiable interpersonal
  stressors
• Confluence of depressive symptoms, increasing
  severity
• Has noted decreased sleep by approximately 12
  hours on occasion my mind wont stop when my
  head hits the pillow
• Has noted panic attacks, generalized anxiety, and
  mood lability woven into depressive symptoms, no
  suicidal ideation, psychotic features, alcohol or
  substance abuse

31
History of Present Illness (cont)

• Although patient maintains normal working hours,
  spends less time creating new menu items
• On days off, has been exercising less and
  becoming socially withdrawn
• Current antidepressant, an SSRI, offers minimal
  symptom relief and may even worsen my anxiety
• Adherent with medication prescribed 8 weeks ago

32
Past Psychiatric History

• Recalls being anxious as a child
• No externalizing behavioral disorder or history
  of trauma
• Index depressive episode as sophomore, age 21
  after breakup with boyfriend
• Depressive episodes typically last 24 months in
  duration with suggestion of worsening in the fall

33
Past Psychiatric History (cont)

• Has received three previous antidepressants, all
  of which she described as not working
• Further history reveals that previous
  antidepressants worsened anxiety
• Has been in therapy on one previous occasion for
  three months, but my therapist didnt understand
  me
• Occasionally takes benzodiazepines when agitation
  is severe
• No prior hospitalization

34
Recent Psychiatric History

• Prior to onset of current depression, patient was
  awarded Chef of the Year by local state licensing
  board
• Was spending most of her social time with friends
  and had recently joined a book club
• Was exercising on a regular basis, and planning a
  mountain bike trip with friends

35
Past Medical History

• Nonsmoker
• Allergic to penicillin
• History of migraines
• No diabetes, obesity, or heart disease
• Menstrual cycle has been chronically irregular

36
Social and Family History

• Father has history of alcohol abuse, mother has
  history of depression patient has two older
  brothers
• Does not know if brothers have been treated for
  mental disorder, but refers to older brother as a
  pot head
• No family history of suicide or schizophrenia
• Born and raised in city currently resides in
• Close relationship with mother, father is
  somewhat distant
• No history of trauma
• Employed as chef for the past seven years
• Currently in a relationship for the past year

37
Mental Status Examination

• Looks stated age although well groomed, appears
  tired and fatigued
• Speech slow, affect congruent with depressed
  mood, decreased range normal thought form no
  suicidal ideation preoccupied with diminished
  interest in her career good insight no gross
  impairment of judgment or cognition

38
Differential Diagnosis

• Major depressive disorder
• Bipolar spectrum disorder
• Anxiety disorder comorbidity
• Mood disorder due to a general medical condition
• Substance induced mood disorder

39
Laboratory Tests

• CBC, electrolytes, renal and liver function all
  within normal range
• TSH above medium but within normal range
• Normal blood glucose and lipids
• BMI 26

40
Clinical Course

• Diagnosis of bipolar NOS was applied due to a
  lack of history of hypomania
• Antidepressant discontinued
• Divalproex refused, concern regarding polycystic
  ovarian syndrome
• Lamotrigine initiated, but discontinued after
  rash despite benign appearance of cutaneous
  reaction
• Olanzapine 10 mg/day provided as mood
  stabilizer
• Cognitive behavioral therapy provided to target
  subsyndromal depressive symptoms
• Exercise encouraged
• Symptom burden considerably reduced, need for
  antidepressants in the future was required
  intermittently

41
Case Summary

• 37-year-old female presenting with depression,
  previously diagnosed with major depressive
  disorder
• Suboptimal trials of antidepressants
• Anxiety and medical comorbidity overlap
• Atypical/seasonal depressive pattern
• Depressive symptoms presage medical service
  utilization
• Menstrual cycle exacerbation

42
Key Messages

• Bipolar spectrum disorder (BSD) presenting as
  depression symptoms/episodes
• Most individuals with BSD underrecognized and/or
  diagnosed with depression
• Anxiety and medical comorbidity differentially
  affect individuals with BSD
• Antidepressants not reliable treatments in BSD,
  potentially harmful
• All depressive presentations to be screened for
  BSD