Dopamine , Depression and Bupropion

BillyPan

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.

HPA axis and Neurotransmitter Stress HPA axis corticotropin-releasing factor amygd

ala, 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.

HPA axis and Neurotransmitter Chronic Stress Excessive glutamate activation of NMDA t

ype glutamate receptor

decrease brain derived neurotrophic factor (BDNF)

degeneration of glial cell

brain atrophy

Pharmacol Biochem Behav 2002;73:147-58.

Brain structural and functional abnormalities in mood disorders

Brain Struct Funct (2008) 213:93–118

Brain structural and functional abnormalities in mood disorders

CMAJ. 2009 February 3; 180(3): 305–313.

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.

Prefrontal Cortext and Ventral Straitum

Dopamine and Serotonin Pathway

Depressive s/s

Dopamine and Substance Abuse

Monoamine neurotransmitter regulation of mood and behavior

Stahl SM. Essential Psychopharmacology. 2000.Foote SL, Aston-Jones GS. Psychopharmacology. 1995: 335-345Nutt DJ et al., J Psychopharmacol 2007, in press [Epub ahead of print,18 Oct 2006]Shelton AJ, Tomarken RC, Psychiatric Services 2000; 52 (11):1469–1478Stahl SM J Clin Psychiatry 2003;64:1145-1146

Dopamineattention

motivationpleasure reward

Dopamineattention

motivationpleasure reward

Noradrenalinealertnessenergy

Noradrenalinealertnessenergy

Serotoninobsessions

compulsions

Serotoninobsessions

compulsions

anxietyanxiety

moodmood

interestinterest

The Dopamine Pathway

SSRI

NDRI

From the study of smoke cessation

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

Wellbutrin, Failed in 1986… Wellbutrin was withdrawal from mark

et 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)

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.

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

Mea

n c

han

ge

fro

m

bas

elin

e at

wee

k 8

n = 263 n = 266 n = 256

–5.2–4.5

–3.6

n = 263 n = 266 n = 2560

–10

–4

–8

–6

–12

–2

Mea

n c

han

ge

fro

m

bas

elin

e at

wee

k 8

HAD Anxiety Subscale ScoreHAD Total Score

–11.1–10.5

–8.1

*

**

*

Clayton et al J Clin Psychiatry, 2006

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 KoreaResponse = 50% reduction in HAMD-17 total scoreRemission = 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)

*

Rem

issi

on

rat

e (%

)

Wellbutrin XL is effective for elderly patients with MDD

***

* p<0.05 significant vs placebo; ** p<0.001 significant vs placebo

43 46

6053

010203040506070

MADRS CGI

% p

ati

ents

Placebo (n=207)

Wellbutrin XL (n=211)

Wellbutrin XL has significantly higher response rates than placebo (LOCF)

MADRS responders: 50% decrease from baselineCGI global improvement responders: score 1 or 2

Chrzanowski W et al., Eur Neuropsychopharmacol 2006; 16 (Suppl 4):S315.

Wellbutrin XL improves low energy and motivation

0

5

10

15

20

25

MEI to

tal sc

ore

m

ean c

hange f

rom

base

line

Placebo(n = 180)

17

24*

*p = 0.001 vs placeboMEI = Motivation and Energy Inventory

Chrzanowski W et al., Eur Neuropsychopharmacol 2006; 16 (Suppl 4): S315.

Wellbutrin XL150-300mg/day

(n = 188)

Wellbutrin XL improves depressive in energy, interest and pleasure

Impro

vem

ent

in s

ym

pto

ms

of

energ

y, in

tere

st a

nd p

leasu

re(I

DS-s

ubse

t#)

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 subscaleJefferson JW et al., J Clin Psychiatry 2006;67:865-873

Comparison of adverse events (%) for Wellbutrin® XL vs the SSRI escitalopram

  Wellbutrin XR150-450mg/day

(n=276)

Escitalopram10-20mg/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

Comparison of adverse events (%) for Wellbutrin® XL vs the SNRI venlafaxine

  Wellbutrin XL150-450mg/day

(n=168)

Venlafaxine XR75-225mg/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

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

PlaceboWellbutrin XLVenlafaxine XL

Overall rates of discontinuation symptoms similar to placebo

(Venlafaxine XR: 21%; Wellbutrin XL: 12%; Placebo: 12%)

Somnolence vs SSRIs

Thase ME et al., J Clin Psychiatry 2005; 66(8):974-81

5

12 *

3†

Inci

den

ce o

f so

mn

ole

nce

as

an A

E (

%)

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

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 placeboAdapted 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

0BMI <22 BMI 22-26 BMI 27 BMI 30

Mean c

hange in b

ody w

eig

ht

(kg)

Weight change during treatment

Orgasm dysfunction vs. SSRI Escitalopram

0

10

20

30

40

Pat

ien

ts (

%)

Week2 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 placeboNo statistical difference between bupropion XL and placebo

Minimal sexual side-effects compared with the SNRI venlafaxine XL

Thase ME et al. J Clin Psychopharmacol 2006; 26, 482-488.

*p0.011 vs venlafaxine XR

-1

*

**

*

*

0

1

PleasureDesire/

FrequencyDesire/Interest Arousal Orgasm

Bupropion XL (n=160)Venlafaxine XR (n=164)

Ad

just

ed m

ean

ch

ang

e fr

om

bas

elin

e 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

Better Adherence with XL Formulation

American Journal of Therapeutics 2007; 14: 241–246

Refill adherence over the study period

% C

ohor

t Rem

aini

ng

*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

Smoking Cessation

Smoking Cessation

Weight Reduction

Improving Cognitive Function

For Bipolar Depression

For Bipolar Depression

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)

In STAR*D Level 2 Switch: Beat CBT

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