THE ROLE OF DOPAMINE IN DEPRESSION

1
THE ROLE OF DOPAMINE IN DEPRESSION

• Dr. Shabeer Ahmed Jeeva
• L.R.C.P., L.R.C.S. (Irel).,
• D. PSYCH (Ottawa) F.R.C.P. (Canada)
• Child and Adult Psychiatrist
• Mississauga, Canada
• jeeva786_at_rogers.com

2
GAUTENG
Dr Shabeer A Jeeva L.R.C.P L R C S (Ireland), D.
Psych (Ottawa),F.R.C.P (Canada) SPECIALIST CHILD
AND ADULT PSYCHIATRIST www.adhdclinicjeeva.com MEL
ROSE ARCH , MORNINGSIDE CLINIC AND GARDEN CITY
CLINIC 011 684 0928/082-9027307
3
(No Transcript)
4
(No Transcript)
5
Diagnosing Depression

• S Sleep disorder
• A Appetite (i.e., weight gain or loss)
• D Dysphoria bad mood, irritability, sadness
• A Anhedonia lack of interest/pleasure in
  usual activities, loss of libido
• F Fatigue
• A Agitation/retardation
• C Concentration diminished
• E Esteem (low self-esteem, feelings of guilt)
• S Suicide

6
(No Transcript)
7
Depression Symptom thatMost Interferes with
Patients Lives
Top Five Symptoms Spontaneously Identified
Respondents
Base Diagnosed with Depression (n434)
Significantly different at gt 95 level of
confidence
8
Population Perspective Problems with Depression

• Even with treatment, outcomes are often
  disappointing and the illness recurs
• less than 40 achieve remission
• individuals with residual symptoms far more
  likely to relapse
• Average number of episodes in a lifetime appears
  to be rising

9
Demographic Characteristics

n
























Diagnosed with Depression Sample
100
434






Male
29
126



Female
71
308















Prevalence of Depression
7










Significantly different at gt 95 level of
confidence
10
Stigma and Attitudes

• In Ontario, half of depressed people NOT in
  treatment cited attitudinal factors, ie stigma, I
  should be able to tough it out, etc Lin
  Parikh, J Affect Disord 1996
• Patients asked about 9 potential causes of
  depression (such as chemical imbalance,
  stressors, genetics, pessimistic tendencies, etc)
  in one Toronto study did NOT identify any one
  cause as particularly dominant
  Srinivasan, Cohen and Parikh, 2003

11
Broad Aspects of Patient Treatment Preferences

• Patients prefer to be treated in primary care
  settingeven if that is the ob-gyn!
• (Parikh et al, Can J Psych 1997 Scholle et
  al, 2003)
• Patients prefer counselling, even if they believe
  anti-depressants may work better (Priest et
  al, BMJ 1996 Unutzer et al, J Am Geriat Soc
  2003)
• Stigma predicts poor compliance
• (Sirey et al, 2001)

12
Population Perspective Problems with Depression

• Prevalence is high, but treatment is low
• In Ontario, about 5 have major depression in a
  year less than half receive any treatment only
  20 medicated (Parikh et al, J Affect Disorders
  1999)
• In US, annual prevalence may approach 8, but
  treatment shows similar low rates of treatment
  (Kessler et al, Arch Gen Psych, 1994)
• Prevalence rising,but psychiatrists falling!

13
Antidepressant pharmacokinetics
Adapted from Stahl et al.
1. Stahl SM, Pradko JF, Haight BR, Modell JG,
Rockett CB, Learned-Coughlin S. A Review of the
Neuropharmacology of Bupropion, a Dual
Norepinephrine and Dopamine Reuptake Inhibitor.
Prim Care Companion J Clin Psychiatry
20046(4)159-166.
14
Potential Clinical Implications of Bupropion SR
Neuropharmacology

• Prodopaminergic Pronoradrenergic
• hedonic capacity energy, cognition,
  motivation
• libido orgasm
• craving melatonin secretion
• cognition

No 5-HT Activity sexual dysfunction weight
gain discontinuation syndrome
15
Section IV Medications and Other Biological
Treatments

• Choosing an Antidepressant
• Optimal Use of Antidepressants
• Maintenance Treatments
• Other Biological Treatments
• Electroconvulsive therapy
• Light therapy
• St. Johns Wort
• Sleep deprivation
• Psychosurgery
• Transcranial magnetic stimulation

16
WELLBUTRIN SR

• WELLBUTRIN SR is the first and only aminoketone
  antidepressant1
• WELLBUTRIN SR affects noradrenergic and
  dopaminergic pathways1
• WELLBUTRIN SR has a unique clinical profile1

1. Stahl SM, Pradko JF, Haight BR, Modell JG,
Rockett CB, Learned-Coughlin S. A Review of the
Neuropharmacology of Bupropion, a Dual
Norepinephrine and Dopamine Reuptake Inhibitor.
Prim Care Companion J Clin Psychiatry
20046(4)159-166.
17
Summary of findings from Weihs et al.

• WELLBUTRIN SR and paroxetine were comparable on
  all measures of efficacy (HAM-D, HAM-A, CGI-S and
  CGI-I) throughout study3
• Because of its favourable side-effect profile,
  bupropion SR may provide a safe and effective
  nonserotenergic treatment alternative 3

3. Weihs KL, Settle EC, Batey SR, Houser TL,
Donahue RMJ, Ascher JA. Bupropion Sustained
Release Versus Paroxetine for the Treatment of
Depression in the Elderly. J Clin Psychiatry
200061(3)196-202.
18
Summary of findings from Fava et al.

• Approximately 60 of depressed patients resistant
  to treatment with fluoxetine experienced a full
  or partial response to WELLBUTRIN SR4
• Bupropion SR should be considered as a
  potential treatment for patients who remain
  depressed despite treatment with SSRIs 4

4. Fava M, Papakostas GI, Petersen T, et al.
Switching to Bupropion in Fluoxetine-Resistant
Major Depressive Disorder. Ann Clin Psychiatry
200315(1)17-22.
19
Antidepressant tolerability profiles
1. Stahl SM, Pradko JF, Haight BR, Modell JG,
Rockett CB, Learned-Coughlin S. A Review of the
Neuropharmacology of Bupropion, a Dual
Norepinephrine and Dopamine Reuptake Inhibitor.
Prim Care Companion J Clin Psychiatry
20046(4)159-166.
Adapted from Stahl et al.
20
WELLBUTRIN SR - a distinct tolerability profile1

• WELLBUTRIN SR the only currently available
  NDRI is as effective as other antidepressants
  but is less likely to cause common antidepressant
  side effects such as sexual dysfunction, weight
  gain and sedation1

1. Stahl SM, Pradko JF, Haight BR, Modell JG,
Rockett CB, Learned-Coughlin S. A Review of the
Neuropharmacology of Bupropion, a Dual
Norepinephrine and Dopamine Reuptake Inhibitor.
Prim Care Companion J Clin Psychiatry
20046(4)159-166.
21
(No Transcript)
22
Improved sexual functioning vs. SSRIs6

• 77 of patients experienced at least one aspect
  of heightened sexual functioning with WELLBUTRIN
  SR6In contrast,
• 73 of patients treated with SSRIs, (including
  fluoxetine, paroxetine and sertraline)
  experienced sexual dysfunction6
• bupropion should be given serious consideration
  as a first-line antidepressant for the treatment
  of depression in sexually active individuals 6

6. Modell JG, Katholi CR, Modell JD, DePalma RL.
Pharmacoepidemiology and Drug Utilization.
Comparative sexual side effects of bupropion,
fluoxetine, paroxetine, and sertraline. Clin
Pharmacol Ther 199761(4)476-487.
23
Summary of findings from Coleman et al.

• Significantly more fluoxetine-treated patients
  experienced orgasm dysfunction than WELLBUTRIN
  SR- or placebo-treated patients (plt0.001)7
• At various time points worsening sexual
  functioning, sexual desire disorder, sexual
  arousal disorder dissatisfaction with sexual
  functioning occurred more frequently with
  fluoxetine than with placebo or WELLBUTRIN
  SR7

7. Coleman CC, King BR, Bolden-Watson C, et al. A
Placebo-Controlled Comparison of the Effects on
Sexual Functioning of Bupropion Sustained Release
and Fluoxetine. Clin Therapeutics
200123(7)1040-1058.
24
Summary of findings from Croft et al.

• Neutral weight anti-craving effects have been
  associated with WELLBUTRIN SR8
• Modest weight loss was observed with long term
  treatment8
• Mean weight reductions were the greatest for
  patients with BMI ? 278
• Normal weight (BMI 22-27) and underweight (BMI lt
  22) patients maintained body weight near baseline
  values during double blind treatment8

8. Croft H, Houser TL, Jamerson BD et al. Effect
on Body Weight of Bupropion Sustained-Release in
Patients with Major Depression Treated for 52
Weeks. Clin Therapeutics 200224(4)662-672.
25
Summary of findings from clinical studies

• Compared to SSRIs, WELLBUTRIN SR was associated
  with significantly lower rates of sedation
  (Pooled analysis of all studies comparing
  bupropion and SSRIs)1
• Unlike other antidepressants, WELLBUTRIN SR was
  not associated with sedation (Results from 3
  randomised, double-masked, multicentre safety
  studies)9
• These characteristics of bupropion SR may be
  particularly important to practitioners who are
  trying to maximise patient compliance 9

1. Stahl SM, Pradko JF, Haight BR, Modell JG,
Rockett CB, Learned-Coughlin S. A Review of the
Neuropharmacology of Bupropion, a Dual
Norepinephrine and Dopamine Reuptake Inhibitor.
Prim Care Companion J Clin Psychiatry
20046(4)159-166. 9. Settle EC, Stahl SM, Batey
SR, Johnston JA, Ascher JA. Safety Profile of
Sustained-Release Bupropion in Depression
Results of Three Clinical Trials. Clin
Therapeutics 199921(3)454-463.
26
WELLBUTRIN SR - favourable side-effect profile11

• Constructed from the 1998 Physicians Desk
  Reference. 11. Dewan MJ, Anand VS. Evaluating the
  Tolerability of the Newer Antidepressants. J Nerv
  Ment Dis 199918796-101.

27
WELLBUTRIN SR - favourable side-effect profile12

• In 2057 depressed patients completing acute phase
  of 8-week open label study, receiving up to 300
  mg WELLBUTRIN SR/day12
• 97 experienced no side-effects or
  side-effects that did not significantly
  interfere with patient functioning
• This favourable side-effect profile was
  particularly beneficial for many of the patients
  who poorly tolerated their previous
  antidepressant 12

12. Dunner DL, Zisook S, Billow AA, Batey SR,
Johnston JA, Ascher JA. A Prospective Safety
Surveillance Study for Bupropion
Sustained-Release in the Treatment of Depression.
J Clin Psychiatry 199859366-373.
28
WELLBUTRIN SR safety profile

• 8-week open label study of 3100 depressed
  patients receiving WELLBUTRIN SR up to 300
  mg/day12
• 54 adverse events, other than seizure, were
  reported, but none considered attributable to
  WELLBUTRIN SR
• Seizure rate well within the range observed with
  other marketed antidepressants

12. Dunner DL, Zisook S, Billow AA, Batey SR,
Johnston JA, Ascher JA. A Prospective Safety
Surveillance Study for Bupropion
Sustained-Release in the Treatment of Depression.
J Clin Psychiatry 199859366-373.
29
WELLBUTRIN SR dosing information

• Full antidepressant effect of WELLBUTRIN SR may
  not be evident until after several weeks of
  treatment
• Gradual escalation to second dose (if required),
  is important to minimise potential side-effects,
  like agitation insomnia that may occur during
  initial days of treatment
• Insomnia may be reduced by avoiding bedtime
  doses
• Treatment in patients with renal impairment
  should be initiated at a reduced dosage

30
Antidepressants c.2004
TCA
SSRI
NDRI

• Amitriptyline
• Imipramine
• Clomipramine
• Trimipramine
• Maprotiline
• Amoxapine
• Nortriptyline
• Desipramine

• Bupropion-SR

• Citalopram PLUS
• Fluoxetine
• Fluvoxamine
• Sertraline
• Paroxetine

NRI

• ? Reboxetine

SARI

• Trazodone
• Nefazodone

NaSSA

• Mirtazapine

31
Choosing an Antidepressant

• All have similar response ratesbut there are
  some target symptom differences
• Minimize side effects
• Look for safety in overdose and interactions

32
Primary NeurotransmitterEffects of
Antidepressants

• NE 5-HT DA
• Bupropion SR ? ?
• SSRIs ?
• Venlafaxine ? ?
• Mirtazapine ? ?
• Desipramine ?

Richelson E. J Clin Psychiatry 199455 Suppl
A34 Stahl S. Essential Psychopharmacology, 2000
33
Dual Mode of Action Norepinephrine Dopamine
34
Double-blind RCTs Comparing Bupropion to TCAs

• Summary
• All trials were acute phase studies and showed no
  differences in efficacy
• Bupropion demonstrated tolerability advantages
  over TCAs

35
Bupropion SR Efficacy vs SSRIs Reduction in
HAM-D Scores
vs Fluoxetine
vs Sertraline
vs Paroxetine
Feighner
Weihs
Kavoussi
Croft
Coleman
(1991)
(1997)
(1999)
(1999)
(2000)
FLUX
BUP
SERT
BUP (IR)
BUP
SERT
BUP
SERT
BUP
PAROX
Baseline
26.1
26
25
25.3
33
33
34.5
34.8
27.5
27.5
Reduction in HAM-D Scores
16
16
16
16
17
17
17
18
20
21
Adapted from Nieuwstraten C. Ann Pharmacother
2001351608
36
Mean Change in Symptoms for Bupropion SR and
Placebo Principal Component Analysis
Domain
Fatigue
Eating
Cognitive
Accessory
Retardation
and Interest
and Weight
Insomnia
Anxiety


Mean Change

plt0.001 p0.003 p0.002
Bupropion SR (n527)

Placebo (n383)
Adapted from Jamerson B. Psychopharmacol Bull
20033767
37
Bupropion SR Efficacy Summary

• Numerous RCTs show acute phase efficacy gt
  placebo TCAs SSRIs
• Prevents relapse up to 1 year vs placebo
• No data on remission or comparisons to other
  novel antidepressants
• Qualitative benefits for energy, cognition,
  motivation, functional status work

38
Bupropion SR MDD Anxiety Summary

• Numerous trials have demonstrated that bupropion
  SR relieves anxiety symptoms in MDD patients
  equivalent to TCAs and SSRIs
• Bupropion SR is an appropriate therapy for use in
  MDD patients with/without coexisting anxiety
  symptoms

39
Seizure Risk With Bupropion SR at300 mg/day is
Comparable to SSRIs/SNRIs at Their Therapeutic
Doses
Antidepressant Seizure rate Bupropion
SR 0.10 Paroxetine 0.15 Sertraline 0.20 Citalop
ram 0.25 Venlafaxine XR 0.26
Adapted from the Compendium of Pharmaceuticals
and Specialties (CPS), 2003
40
How Can Seizure Risk May be Minimized with
Appropriate Dosing?

• Keep total daily dose lt300 mg/d
• No single dose gt150 mg
• Take doses 8 hours apart (eg, breakfast, dinner)
• Start at 150 mg OD x 7-11 days

Wellbutrin SR (bupropion HCI) Product Monograph,
2/7/03
41
Antidepressant Response

• Frequently, patients begin to respond in the
  first 1-2 weeks
• Do something by Week 4 if they are
  non-responders
• Helpful to define partial vs. non-response

42
Optimizing Antidepressants

• If you think you are getting a partial response,
  optimize dose
• If response but side effects, stay in class
  unless sexual side effects
• Scant or no response, change class

43
Refractory Strategies in Guidelines

• Combine
• SSRI TCA
• SSRI RIMA
• SSRI Tryptophan
• Bupropion SSRI
• Venlafaxine Bupropion or SSRI
• MAOI TCA

• Augment
• Lithium
• Triiodothyronine (T3)
• Atypical antipsychotics
• Buspirone
• Amphetamines
• Pindolol

44
WELLBUTRIN SR contraindicated in patients

• receiving ZYBAN
• with seizure disorders
• with current or previous diagnosis of bulimia or
  anorexia nervosa
• on monoamine oxidase inhibitors (MAOIs)
• undergoing abrupt alcohol or sedative
  discontinuation
• severe liver disease
• with known hypersensitivity to any component of
  the preparation

45
OTHER INDICATIONS

• 1.FATIGUE STATES
• fibromyalgia/chronic fatigue
  syndrome/multiple sclerosis
• 2.ANTIDEPRESSANT SIDE-EFFECTS
• tiredness/libido/weightgain
• 3.ADULT ADHDdrug of choice

46
Most Improved Symptoms
Insomnia
Loss of Interest/Pleasure
Suicidal/Suicide Ideation
Physical Symptoms of Anxiety
Fatigue/Lack of Energy
Tense/Nervous/Irritable
Guilt/Self-Criticism
Impaired Concentration/Decision-Making
Excessive Worry
Depressed Mood
Sleeping Too Much
Pain/Muscle Aches
Base Treated with antidepressants only during
most recent episode of depression (n109)
Significantly different from all ratings except
loss of interest, suicidal and physical anxiety
at gt 95 level of confidence
Significantly different from all ratings
except sleeping too much at gt 95 level of
confidence
47
WELLBUTRIN SR - summary

• The first aminoketone (NDRI) antidepressant1
• As effective as other antidepressants2,3,4
• Improved sexual functioning vs. SSRIs6,7
• Not commonly associated with weight gain8
• Not associated with sedation1,2,3,7,9,10
• Safe when used in recommended therapeutic doses12

48
(No Transcript)
49
Famous People with Attention Deficit and
Learning Disorders

• Albert Einstein
• Thomas Edison
• Gen. George Patton
• John F. Kennedy
• Bruce Jenner
• Eddie Rickenbacker
• Harry Belafonte
• Walt Disney
• Steve McQueen
• George C. Scott
• Tom Smothers
• Suzanne Somers
• Jules Verne
• Magic Johnson
• Carl Lewis

• Nelson Rockefeller
• Sylvester Stallone
• Cher
• Gen. Westmoreland
• Charles Schwab
• Danny Glover
• John Lennon
• Greg Louganis
• Winston Churchill
• Henry Ford
• Robert Kennedy
• George Bernard Shaw
• Beethoven
• Hans Christian Anderson

• Galileo
• Mozart
• Leonardo da Vinci
• Whoppi Goldberg
• Tom Cruise
• Henry Winkler
• F. Scott Fitzgerald
• Robin Williams
• Louis Pasteur
• Werner von Braun
• Dwight D. Eisenhower
• Lindsay Wagner
• Alexander Graham Bell
• Woodrow Wilson

50
????????????????
51
(No Transcript)