Dopamine, Depression and bupropion

1. Dopamine , Depression and
Bupropion
BillyPan

2. HPA axis
CMAJ. 2009 February 3; 180(3): 305–
313.
The hypothalamic–pituitary–adrenal axis.
This system is activated by stress directly at the
level of the hypothalamus or indirectly at the level
of the amygdala.
Chronic stress increases the level of corticotropin-
releasing factor and cortisol and decreases
expression of corticotropin-releasing factor type 1
receptors and glucocorticoid receptors.
Stress-and depression-associated changes at the
level of the hippocampus in particular are thought
to underlie the structural changes seen in this
brain region, which in turn may contribute to
chronic disinhibition of the hypothalamic–
pituitary– adrenal axis.

3. HPA axis and
Neurotransmitter
 Stress  HPA axis  corticotropin-releasing factor 
amygdala, hippocampus, ect.
 These neurons may also contribute to activation of the serotonin
and norepinephrine systems.
 Reciprocal connections between the norepinephrine system and
the hypothalamus create a feed-forward cascade in which
stress progressively activates corticotropin-releasing factor and
norepinephrine signalling.
 Activation of this system is thought to increase vigilance and
fear.
Pharmacol Biochem Behav 2002;73:147-58.

4. HPA axis and
Neurotransmitter
 Chronic Stress  Excessive glutamate activation of NMDA
type glutamate receptor
 decrease brain derived neurotrophic factor (BDNF)
 degeneration of glial cell
 brain atrophy
Pharmacol Biochem Behav 2002;73:147-58.

5. Brain structural and functional
abnormalities in mood disorders
Brain Struct Funct (2008) 213:93–118

6. Brain structural and functional
abnormalities in mood disorders
CMAJ. 2009 February 3; 180(3): 305–313.

7. HPA axis and
Neurotransmitter
 Stress  Amygdala
  increse dopamine in Prefrontal Cortext and Ventral Straitum
  altering striatal levels of BDNF.
 Acute irritable
 Chronic anhedonia
Pharmacol Biochem Behav 2002;73:147-58.

8. Prefrontal Cortext and Ventral
Straitum

9. Dopamine and Serotonin Pathway

10. Depressive s/s

11. Dopamine and Substance
Abuse

12. Monoamine neurotransmitter
regulation of mood and behavior
Stahl SM. Essential Psychopharmacology. 2000.
Foote SL, Aston-Jones GS. Psychopharmacology. 1995: 335-345
Nutt DJ et al., J Psychopharmacol 2007, in press [Epub ahead of print,18 Oct 2006]
Shelton AJ, Tomarken RC, Psychiatric Services 2000; 52 (11):1469–1478
Stahl SM J Clin Psychiatry 2003;64:1145-1146
Dopamine
attention
motivation
pleasure
reward
Noradrenaline
alertness
energy
Serotonin
obsessions
compulsions
anxiety
mood
interest

13. The Dopamine Pathway

14. SSRI

15. NDRI

16. From the study of smoke
cessation

17. Antidepressants - History
 1958 Monoamine oxidase inhibitors (MAOIs)
 1958 Tricyclics (TCA’s)
 1982 Trazodone (Deseryl)
 1988 Fluoxetine (Prozac)
 1989 Bupropion (Wellbutrin IR) Tid
 1994 Nefazodone (Serzone)
 1994 Venlafaxine (Effexor)
 1996 Mirtazapine (Remeron)
 1996 Bupropion (Wellbutrin SR) Bid
 2003 Bupriopion (Wellbutrin XL) Qd

18. Wellbutrin, Failed in 1986…
 Wellbutrin was withdrawal from market
due to significant incidence of seizure.
 Risk of seizure was found to highly
dose–dependent.
 Wellbutrin was reintrodued in 1989 for
limit maximum dose of 450mg.
(originally recommended dosage was
400-600mg)

19. Wellbutrin seizure incidence
 Wellbutrin®
XL is associated with a dose-related risk of
seizure but risk is relatively low- overall incidence in clinical
trials (up to 450mg/day) is ~0.1%1
and is similar to other
newer antidepressants (0-0.4%)2
 Incidence of first seizure in the general population is
estimated to be 0.07 to 0.09%2
 Wellbutrin®
XL is contraindicated in patients with a current
seizure disorder or any history of seizures1
 Wellbutrin®
XL is contraindicated in patients taking
medicinal products containing bupropion, as the incidence
of seizures is dose-dependent1
1. Wellbutrin XL Prescription Information.
2. Montgomery SM Int J Clin Pract 2005;59(12):1435-1440.

20. Efficacy of Wellbutrin®
XL
vs. Escitalopram
HAD = Hospital Anxiety and Depression Scale
*P<0.05 vs placebo.
Bupropion XL Escitalopram Placebo
0
–10
–4
–8
–6
–12
–2
Meanchangefrom
baselineatweek8
n = 263 n = 266 n = 256
–5.2
–4.5
–3.6
n = 263 n = 266 n = 256
0
–10
–4
–8
–6
–12
–2
Meanchangefrom
baselineatweek8
HAD Anxiety Subscale ScoreHAD Total Score
–11.1–10.5
–8.1
*
**
*
Clayton et al J Clin Psychiatry, 2006

21. Efficacy of Wellbutrin®
XL
vs. venlafaxine XL
Response and remission rates from the US clinical trial
Venlafaxine XR
* Statistically significant: odds ratio 1.75, 95% CI 1.04, 2.93
# Includes doses above the maximum recommended dose in South Korea
Response = ≥50% reduction in HAMD-17 total score
Remission = HAMD-17 total score ≤7
Thase ME et al. J Clin Psychopharmacol 2006: 26:482-488
0
10
20
30
40
50
60
Response Remission
Bupropion XL
(150-450mg/day#)
(75-225mg/day)
*
Remissionrate(%)

22. Wellbutrin XL is effective for
elderly patients with MDD
**
*
* p<0.05 significant vs placebo; ** p<0.001 significant vs placebo
43 46
60
53
0
10
20
30
40
50
60
70
MADRS CGI
%patients
Placebo (n=207)
Wellbutrin XL (n=211)
Wellbutrin XL has significantly higher response rates than placebo (LOCF)
MADRS responders: ≥50% decrease from baseline
CGI global improvement responders: score 1 or 2
Chrzanowski W et al., Eur Neuropsychopharmacol 2006; 16 (Suppl 4):S315.

23. Wellbutrin XL improves low
energy and motivation
0
5
10
15
20
25
MEItotalscore
meanchangefrombaseline
Placebo
(n = 180)
17
24*
*p = 0.001 vs placebo
MEI = Motivation and Energy Inventory
Chrzanowski W et al., Eur Neuropsychopharmacol 2006; 16 (Suppl 4): S315.
Wellbutrin XL
150-300mg/day
(n = 188)

24. Wellbutrin XL improves depressive
in energy, interest and pleasure
Improvementinsymptomsof
energy,interestandpleasure
(IDS-subset#
)
Placebo Wellbutrin XL
0
2
4
6
8
5.3
6.7
*
Some patients in this analysis received doses of Wellbutrin that are above the licensed dose
* p=0.007 significant improvement vs placebo
#patient rated subscale
Jefferson JW et al., J Clin Psychiatry 2006;67:865-873

25. Comparison of adverse events (%) for
Wellbutrin®
XL vs the SSRI escitalopram
Wellbutrin XR
150-450mg/day
(n=276)
Escitalopram
10-20mg/day
(n=281)
Placebo
(n=273)
Dry mouth 22% 13% 11%
Fatigue 4% 14% 6%
Insomnia 14% 10% 8%
Constipation 9% 3% 6%
Somnolence 3% 8% 5%
Decreased
appetite
5% 6% 4%
Nasopharyngitis 5% 5% 3%
Irritability 5% 1% 4%
Yawning <1% 5% 1%
Clayton AH et al.,J Clin Psychiatry 2006;67(5):736-46
Some patients in this analysis received doses of Wellbutrin that are
above the licensed dose

26. Comparison of adverse events (%) for
Wellbutrin®
XL vs the SNRI venlafaxine
Wellbutrin XL
150-450mg/day
(n=168)
Venlafaxine XR
75-225mg/day
(n=174)
Dry mouth 24% 29%
Nausea 15% 26%
Nasopharyngitis 10% 5%
Diarrhoea 5% 10%
Decreased
appetite
4% 9%
Somnolence 1% 7%
Sedation 1% 6%
Yawning 0% 7%
Thase ME et al., J Clin Psychopharmacol 2006;26:482-88
Some patients in this analysis received doses of bupropion that are above the maximum
licensed dose for Taiwan

27. Wellbutrin XL has similar rates of
discontinuation symptoms to placebo
GSK data on file
Discontinuation symptoms during taper and follow-up periods
% of patients
0 1 2 3 4 5
Nausea
Irritability
Insomnia
Dizziness
Headache
Placebo
Wellbutrin XL
Venlafaxine XL
Overall rates of discontinuation symptoms similar to placebo
(Venlafaxine XR: 21%; Wellbutrin XL: 12%; Placebo: 12%)

28. Somnolence vs SSRIs
Thase ME et al., J Clin Psychiatry 2005; 66(8):974-81
5
12 *
3†
Incidenceofsomnolenceas
anAE(%)
Placebo Pooled SSRIs Bupropion
(n=524) (n=758) (n=748)
*p<0.001 significantly higher incidence vs placebo
†p<0.001 significantly lower incidence vs pooled SSRIs
0
2
4
6
8
10
12
14
Some patients in this analysis received doses of Wellbutrin that are above the maximum licensed dose
for South Korea

29. 
Mean change in body weight at study endpoint for patients receiving
Wellbutrin SR as a function of baseline body mass index (BMI)
Patients who had responded to 8 weeks of open-label treatment with bupropion (SR)
followed by 44 weeks of double-blind treatment with bupropion (150mg SR bid) or
placebo
Adapted from Croft H et al., Clin Ther 2002;24;662-672
-0.1
-0.6
-1.4
-2.4
-3
-2.5
-2
-1.5
-1
-0.5
0
BMI <22 BMI 22-26 BMI ≥27 BMI ≥30
Meanchangeinbodyweight(kg)Weight change during treatment

30. Orgasm dysfunction vs. SSRI Escitalopram
0
10
20
30
40
Patients(%)
Week
2 4 6 8
30%
15%
9%
†
†
†
†
*
1
Clayton AH et al., J Clin Psychiatry 2006;67:736-746.
Bupropion XL (n=263)
Escitalopram (n=266)
Placebo (n=256)
*p < 0.01 Escitalopram vs bupropion XL and placebo
†p < 0.001 Escitalopram vs bupropion XL and placebo
No statistical difference between bupropion XL and placebo

31. Minimal sexual side-effects compared
with the SNRI venlafaxine XL
Thase ME et al. J Clin Psychopharmacol 2006; 26, 482-488.
*p≤0.011 vs venlafaxine XR
-1
*
*
*
*
*
0
1
Pleasure
Desire/
Frequency
Desire/
Interest Arousal Orgasm
Bupropion XL (n=160)
Venlafaxine XR (n=164)
Adjustedmeanchangefrombaseline
CSFQ Subscale Mean
Change Scores
(Average of Weeks 5-12)
Improvement
Some patients in this analysis received doses of Wellbutrin®
XL that are above the licensed dose

32. Better Adherence with XL
Formulation
American Journal of Therapeutics 2007; 14: 241–246
Refill adherence over the study period
%CohortRemaining
*p<.0001 bupropion XL versus bupropion SR
++p<.0005 bupropion XL versus bupropion SR
+p<.005 bupropion XL versus bupropion SR
Number of Refills for index Product

33. Smoking Cessation

34. Smoking Cessation

35. Weight Reduction

36. Improving Cognitive Function

37. For Bipolar Depression

39. For Bipolar Depression

41. How Effective is an SSRI in Real
World Practice?
 ~1/3 met criteria for remission (HAM-D ≤ 7)
 ~ 1/2 met criteria for response (≥ 50%
decrease in depressive severity)
(Trivedi et al, Am J Psychiatry, 2006)

42. In STAR*D Level 2 Switch:
Beat CBT

43. In STAR*D Level 2 augmentation: :
lead to 46% remission