Burden of Bipolar Depression Differential Diagnosis of Bipolar Depression Management of Bipolar Depression

1. Mohamed Ibrahim
February 2021

2. Challenges
Burden of Bipolar Depression
Differential Diagnosis of Bipolar Depression
Management of Bipolar Depression

3. Bipolar and Related Disorders
(7 disorders)

4. The Burden of Bipolar Depression

5. Asymptomatic
Depressed
Manic/hypoman
% of Weeks
146 bipolar I patients
followed 12.8 years
86 bipolar II patients
followed 13.4 years
53%
32%
9%
6%
46%
50%
1% 2%
Judd et al (2002) Archives of General
Psychiatry (59) 530-537
Judd et al (2003) Archives General
Psychiatry. (60) 261-269
Cycling / mixed

6. High Suicide Risk
Bipolar Disorder

7. High Suicide Risk
Estimated annual suicide rates
Miller et al.,Journal of Affective Disorders 2014
Attempted Suicide Death by Suicide
Bipolar Disorder 3.9% 1.4%
General Population 0.5% 0.02%

8. High Suicide Risk
Risk of suicide is higher during:
• Bipolar Depression ˃ Unipolar Depression
• Bipolar Depression ˃ Bipolar Mania
Depressive episodes become more predominant
later on the course of the disease.

9. 51
46
39
10 8
0
10
20
30
40
50
60
Percent of
Patients
Disorders
Anxiety
Substance Use
Psychosis
ADHD
Eating
Kogan et al., 2004

10. Comorbid medical illness in bipolar disorder

11. Bipolar versus Unipolar Or Bipolar

13. Wrong Diagnosis = Wrong Treatment
Unopposed
Antidepress
-ants
Trigger
Mania
And
Anxiety
Poor
Response
Increase
Risk Of
Suicide
Induce
Rapid
Cycling
Unopposed
Antidepressants
in Bipolar
Depression

14. BAD versus BPD
Patients with borderline personality disorder are at high
risk of being misdiagnosed with bipolar disorder.
(Ruggero, et al 2009)

15. Management of Bipolar Depression
Treatment of bipolar depression is far less well
investigated than unipolar depression, particularly
for long-term prophylaxis.

16. Management of Bipolar Depressive
Episode
 Psychotropics
 Antidepressants
 Mood stabilizer
 Antipsychotic
 Nonpharmacological treatments
 Psychotherapy
 Adjunctive strategies
 Complementary therapies

17. Antidepressants
There is continued controversy about the value and
risks of antidepressant drugs in bipolar depression
(McGirr et al. 2016).

18. Antidepressants
Risks of using antidepressants in bipolar depression
 Mood-switches
 Worsening of agitation, anger, or dysphoria
 Induce rapid cycling
 Increase risk of suicide
(Tondo et al. 2013).

19. Antidepressants and mood
switching
Switching can happen spontaneously
 TCAs (7–11%)
 Venlafaxine (13–15%)
 SSRIs or bupropion 1.16%
Switching is more common with BD I than BD II
Amongst the SSRIs fluoxetine seems to be less likely to cause
switching
(Leverich et al., 2006; Vázquez et al., 2013; Amsterdam and Shults, 2010a)

20. Antidepressants should be avoided
in these cases
 During manic episodes
 During depressive episodes with mixed features.
 In the presence of psychomotor agitation or rapid
cycling.
 History of “Antidepressant switching”
(Tondo et al. 2013; Pacchiarotti et al., 2013a, 2013b; Yatham et al. 2018)

21. Mood stabilizers
 Lithium
 Valproate
 Carbamazepine
 lamotrigine

22. Lithium
 Lithium remains virtually untested for acute
bipolar depression
 Some long-term effectiveness against recurrences
of bipolar depression and greater prophylactic
effects against [hypo] mania
 May be beneficial in mixed episodes
 Lithium may reduce risk of suicide in BD patients
(Young et al. 2010; Sani and Fiorillo 2019; Song et al. 2017)

23. Valproate
 Limited benefit in acute bipolar depression
 May be used as adjunctive medication
 Possible value in the maintenance phase
(prophylaxis against depression)
Sodium valproate versus Divalproex sodium
(Bond et al., 2010; Ghaemi et al., 2007; Muzina et al., 2011)

24. Carbamazepine
 Less effective than lithium
 It is probably better suited to patients with mixed
features
 May be useful in combination with lithium,
especially where there is marked mood instability
 Unfavorable side effect profile
(Weisler et al., 2004; Pratoomsri et al., 2006; Vieta et al., 2008a).

25. Lamotrigine
 Lamotrigine is FDA-approved for long-term
prophylaxis in BD
 Partial effectiveness against recurrences of
depression but little efficacy against acute or
recurrent mania
 Seems to have better utility in bipolar II
depression.
(Frye et al. 2011; Baldessarini 2013; Geddes and Miklowitz 2013)

26. Second Generation
Antipsychotic
 Lurasidone, Cariprazine, Olanzapine/Fluoxetine,
and Quetiapine are the only FDA approved
medicines for short-term treatment of bipolar
depression.
(Baldessarini 2013; Earley et al. 2019; Ragguett and McIntyre 2019).

27. Quetiapine
 Quetiapine has outperformed placebo consistently
in several trials, with similar results for doses of
300 vs. 600 mg/day, and only the lower dose is
FDA-approved
 (McElroy et al. 2010).

28. Lurasidone
 Lurasidone has shown efficacy in the treatment of
acute bipolar depression, both as monotherapy
and as an adjunct to lithium or valproate with
better tolerability
(Loebel et al., 2014a).

29. Olanzapine-Fluoxetine
 Olanzapine-fluoxetine combination was superior
to placebo, whereas olanzapine alone was less
effective.
(Tohen et al. 2003)

30. Cariprazine
 Cariprazine, at both 1.5 mg/day and 3.0 mg/day,
was effective, generally well tolerated, and
relatively safe in reducing depressive symptoms in
adults with bipolar I depression.
 (Earley et. al., 2019)

31. Clozapine
• Clozapine is widely regarded as an option for treating
severe refractory bipolar disorder. However, its
significant side effects and ongoing need for
monitoring limit its use long term.
• There is evidence for its anti-suicidal, anti-aggressive
properties and efficacy in substance use comorbidities.
(Alina Wilkowska 2019)

34. Adjunctive Strategies
 Ketamine
 Agomelatine
 Apimostinel
 Rapastinel
 Brexanolone
 Pramipexole
 Modafinil
 Glutamate antagonists (Memantine/Riluzole)
Fornaro et al., 2013; Martinez Botella et al. 2017; Wilkinson and Sanacora 2019

35. Ketamine
 Treatment resistant depression along with
mitigation of suicidality
 The effects are short-term and often transient.
(McCloud et al., 2015; Wilkinson and Sanacora 2019)

36. Complementary Therapies
 Thyroid hormones
 Omega-3-fatty acids
 N-acetyl cysteine (NAC)
 Chromium
(Berk et al., 2008a; Sarris et al., 2012; Sylvia et al., 2013)

37. Combination Therapy
Whereas monotherapy is the preferred strategy for treating
major depression, the effective treatment of bipolar
depression often requires combinations of medications. The
second generation antipsychotics and mood stabilizing
agents with efficacy as monotherapy agents can be combined
or used in conjunction with antidepressants.

39. Nonpharmacological Treatments
 ECT
 rTMS
 Intense light Therapy
 Sleep Deprivation
 Vagal Nerve Stimulation

40. ECT
 Acute bipolar depression is responsive to ECT; rate
may be higher than unipolar depression.
 Especial value in acutely depressed patients,
patients who are experiencing substantive suicidal
ideation, and when there are catatonic features.
 No difference in response rate between unilateral,
bitemporal and bifrontal ECT.
 ECT-induced mania (continue / discontinue)
(Kellner et al., 2010; Perugi et al. 2017; Bahji et al. 2019)

42. Psychotherapy
 Cognitive-Behavioural Therapy (CBT)
 Interpersonal and Social Rhythm Therapy (IPSRT)
 Family-Focused Therapy (FFT )
Helpful in both the acute episodes and over the maintenance
phase (BD I & BD II)
Can be used alone or added to pharmacological treatment.
(Miklowitz et al., 2007; National Collaborating Centre for Mental Health (NCCMH), 2014)

43. Psychological interventions

44. BD I Depression versus BD II
Depression
 The risk of switch is higher in BD I depression
 Lithium and sodium valproate are less suited to relieving
mood instability in BD II as compared to their role in BD I.
 Antidepressants may be used as monotherapy in BD II
depression (modest evidence).
 Quetiapine and Lamotrigine are the most favored in BD II
 Irreversible MAOIs can be used in resistant cases of BD II
(under cover of atypical antipsychotic or mood stabilizer)
(Amsterdam et al., 2015)