This document discusses major depressive disorder (MDD) and the role of dopamine in depression. It provides the following key points: 1. MDD is a heterogeneous disorder with varying symptom profiles between individuals and episodes. Dopamine is involved in motivation, pleasure, attention, and mood. Reduced dopamine release may contribute to the pathophysiology of depression. 2. Neuroimaging studies have found elevated striatal D2 receptors in depressed patients, possibly reflecting compensatory up-regulation due to reduced dopamine transmission. Positron emission tomography studies have also found reduced dopamine transporter binding and striatal uptake in depressed patients. 3. Dopamine is involved in neurocircuitry implicated in MDD symptoms like anhed

2. 2

3. Dr. M. Nasar Sayeed Khan
Associate Professor and Head Department of
Psychiatry,
SIMS and SHL.
nasarsayeed@yahoo.com
A Presentation

4. Definition
DSM-IV: Major depressive episode
Criteria for the Diagnosis of an Episode of Major Depression (adapted from
DSM-IV)
5 or more symptoms nearly every day for 2 weeks with at least one of the symptoms being either
depressed mood or diminished interest or pleasure:
 Depressed mood most of the day nearly every day
 Markedly diminished interest or pleasure in all or almost all activities
 Clinically significant weight loss in the absence of dieting or weight gain (e.g., a change of more than 5% in body
weight in a month) or a decrease in appetite
 Insomnia or hypersomnia
 Observable psychomotor agitation or retardation
 Fatigue or loss of energy
 Feelings of worthlessness or excessive or inappropriate guilt
 Diminished ability to think or concentrate, or indecisiveness
 Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, a specific plan for committing
suicide, or a suicide attempt
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) system
4

5. Major depression: A heterogeneous DSM-IV disorder
Patient A Patient B
• Depressed mood • Loss of pleasure
• Insomnia • Hypersomnia
• Appetite loss • Weight gain
• Poor concentration • Fatigue
• Agitation • Retardation
5

6. Burden of major depression – Predicted global impact
in 2020
1. Ischaemic heart disease
2. Major depression
Rank
order of 3. Road traffic accidents
disease
burden 4. Cerebrovascular disease
5. Chronic obstructive pulmonary disease
6. Lower respiratory infections
World Bank’s Burden of Disease Estimates 1996: Murray & Lopez eds. The global burden of disease. Boston, MA: Harvard University
Press for the WHO.
6

7. MDD: Lifetime recurrence risk
1. Kupfer DJ. J Clin Psychiatry 1991;52(suppl 5):28-34;
2. Depression Guideline Panel. J Amer Acad Nurse Practitioners 1994;6:224-38.
MDD Major Depressive Disorder
7

8. Comorbidity of current depression and anxiety
WHO Primary Care Study
Current Current
depressive anxiety
disorder* 7.1% 4.6% 5.6% disorder**
(11.7%) (10.2%)
*Depressive episode or dysthymia;
**GAD, panic disorder or agorophobia Sartorius N et al. Br J Psychiatry 1996;168(Suppl 30):38-43
8

9. Prevalence of MDD
US National Comorbidity Survey Replication (NCS-R)
• N=9090 aged 18+; USA
• Prevalence of MDD
– Lifetime: 16.2% (95% CI 15.1,17.3)
– 12-month: 6.6% (95% CI 5.9, 7.3)
(using QIDS-SR: 10.4% mild; 38.6% moderate; 38.0% severe; 12.9% very severe)
• 72.1% lifetime cases had comorbid CIDI/DSM-IV disorders
• 78.5% 12-month cases had comorbid CIDI/DSM-IV disorders
• 51.6% of 12-month cases received health care treatment for MDD
BUT
• Treatment was adequate in only 41.9% of these cases, resulting in 21.7% of 12-
month MDD being adequately treated
Kessler RC et al. JAMA 2003;289:3095-105.
Quick Inventory of Depressive Symptomatology–Self Report (QIDS-SR)
NCS-R National Comorbidity Survey Replication
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) system
Composite International Diagnostic Interview (CIDI
9

10. Depression and anxiety symptoms: Discrete entities
or a shared spectrum?
• Depressive and anxiety disorders frequently co-occur1
• Possible relationships between depression and anxiety
include2:
– Anxiety and depression are two separate entitles
– Both anxiety and depression are reflections of the same phenomenon
– There is a common factor for both anxiety and depression (e.g. stress,
negative affectivity, or vulnerability)
• Because of the overlap in symptoms and comorbidity, it is
helpful to think about depression and anxiety on a spectrum1
• The shared spectrum has implications for common treatment
approaches1
1. Stahl SM et al. J Clin Psychiatry 1993;54:33-8.
2. Levine J et al. Depress Anxiety 2001;14:94–104;
10

12. Diagnosis of anxious depression –
Different scenarios
• Anxiety and depression are classically viewed as discrete entities; however, MDD is
increasingly recognized as a concomitant comorbid illness with anxiety disorders
 Definitions cover situations where
symptoms of depression & anxiety meet
 Full criteria for depressive and anxiety
disorders (comorbid)
 Both are sub-syndromal (mixed anxiety
depression [MADD]) A
 Full criteria for MDD but with sub-syndromal
anxiety symptoms B
 Full criteria for anxiety disorder but sub-
syndromal depressive symptoms C
Stahl SM et al. J Clin Psychiatry 1993;54:33-8.
12

13. Diagnosing & differentiating:
Mixed anxiety depression
DSM-IV-TR, 4th edition, 2000
13

14. Diagnosing & differentiating:
MDD with sub-syndromal anxiety
• Sub-threshold anxiety occurs commonly with MDD; anxiety
commonly precedes MDD1
• High frequency of diagnostic overlap between both conditions
warrants routine assessment for MDD in patients with signs of
anxiety, and vice versa1
• Recognizing sub-syndromal symptoms of anxiety may help
identify patients vulnerable to psychosocial stressors2
– Behavioural interventions may help prevent development of severe and
disabling anxiety2
– Anxiety is often confused with lifestyle issues, problems adjusting to
daily life and self-actualization issues2
1. Wittchen HU et al. Hum Psychopharmacol Clin Exp 2001;16:S21-S30; 2. Stahl SM et al. J Clin Psychiatry 1993;54:33-8 .
14

15. Diagnosing & differentiating:
Anxiety with sub-syndromal
depression
• When anxiety is predominant presenting condition, symptoms may
include fear and non-specific worry accompanied by inappropriate
thoughts and actions1
– Physiological symptoms with motor tension and autonomic
hyperactivity, such as repetitive foot movements, are often present 1
• Depressive disorder may be suspected if patient has visited GP
frequently with repeated, non-specific, medically unexplained
physical complaints2
• Differentiating anxiety symptoms associated with medical
conditions from those caused by anxiety disorders can be difficult1
– Medical condition-associated anxiety may occur after 35 years of age
and in the absence of personal or family history of anxiety disorders 1
1. Mynatt S, Cunningham P. Nurse Pract 2007;32 (8):28-36.
2. Howland RH, Thase ME. The Medical Library 2005 http://www.medical-library.org/j_psych/depression_and_anxiety.htm
15

16. Screening for depression and anxiety (2)
• Mixed anxiety depression
– Symptoms include ≥1 physical symptom (e.g., pains, poor sleep,
fatigue) plus anxiety and depressive symptoms present for >6
months1
• MDD with sub-syndromal anxiety
– Screening for depression recommended if patient presents at ≥3
visits with recurrent physical symptoms (e.g., headache,
fatigue),2
• Anxiety disorder with sub-syndromal depressive disorder
– Risk factors for anxiety disorders include female, perinatal risk
factors, parental history of mental disorder, poor financial
situation2; sub-syndromal features of depression may include
tearfulness, anticipating the worst, hopelessness and pessimism
about the future3 – Mental Health 2005 http://www.library.nhs.uk/mentalhealth/viewresource.aspx?resid=82618;
1. Jenkins R. NHS Evidence
2. Mynatt S, Cunningham P. Nurse Pract 2007 32:28-36; 3. Howland RH, Thase ME. The Medical Library 2005 http://www.medical-
library.org/j_psych/depression_and_anxiety.htm.
16

17. Current and lifetime prevalence of anxiety disorders
in depressed subjects
Anxiety disorder*,1 Current prevalence (%) Lifetime prevalence (%)
Any 57.4 65.7
Specific phobia 13.7 15.0
Social phobia 33.0 35.7
OCD 9.9 12.6
GAD 15.0 15.0
PTSD 13.4 24.1
Panic disorder
Without agoraphobia 2.9 4.0
With agoraphobia 14.2 19.3
*According to DSM-IV. N=373
 In a survey of over 8000 adults in Great Britain, the 1-month prevalence of mixed anxiety
depression (on the basis of a score >12 on the Clinical Interview Schedule – Revised [CIS–R])
was 8.8%2
1. Table adapted from Zimmerman M et al. Am J Psychiatry 2000;157:1337-40;
2.. Das-Munshi J et al. Br J Psychiatry 2008;192:171-7.
17

18. Greater number of suicide attempts in women with
MDD when PTSD is comorbid
Telephone survey of 4008 US women Cougle JR et al. Depress Anxiety 2009;26:1151–7.
18

19. Higher probability of recovery from comorbid MDD
than from anxiety disorders (except panic disorder)
Prospective, naturalistic, longitudinal (12 year) study (HARP)
Recovery: at least 8 consecutive weeks with at most residual symptoms
Bruce et al. Am J Psychiatry 2005;162:1179-87.
19

20. High probability of recurrence of comorbid MDD
following recovery
Prospective, naturalistic, longitudinal (12 year) study (HARP)
Recurrence: full diagnostic criteria for minimum period (2 weeks, other than GAD)
Bruce et al. Am J Psychiatry 2005;162:1179-87.
20

21. Key issues in managing MDD
• Heterogeneous disorder: symptom profiles vary widely
among individuals and between episodes1,2
• Response to antidepressants is inconsistent and
unpredictable1,2
• Residual symptoms are common3,4
• Side-effects negatively impact compliance and long-term
outcome5,6
1. Belmaker RH, Agam G. N Engl J Med 2008;358:55−68. 2. Stahl SM et al. J Clin Psychiatry 2003;64(Suppl 14):6−17.
3. Nierenberg AA et al. J Clin Psychiatry 1999;60:221−5. 4. Nelson JC et al. J Clin Psychiatry 2005;66:1409−14.
5. Zajecka JM. J Clin Psychiatry 2000;61(Suppl 2)20-5; 6. Lin EHB et al. Medical Care 1995;33:67-74.
21

23. Monoamine neurotransmitter regulation
of mood and behaviour
Dopamine Interest Noradrenaline
Motivation Alertness
Pleasure Attention
Energy
Reward
Mood
Anxiety
Serotonin
Obsessions
Compulsions
Nutt DJ. J Clin Psychiatry 2008;69(Suppl E1):4-7.
23

24. Dopamine and anhedonia
Role of dopamine in depression
• Impaired dopamine release is proposed to contribute to the
pathophysiology of depression
• Evidence from clinical investigations support the finding that depressed
patients have reduced cerebrospinal levels of homovanillic acid (HVA), the
major metabolite of dopamine in the CNS
• Animal behavioural models also find an association of depressive
behaviours with altered dopamine functioning of the mesolimbic pathway
Dunlop BW, Nemeroff CB. Arch Gen Psychiatry 2007;64:327-37.
24

25. Role of dopamine in depression
• Dopamine is synthesized in the
cytoplasm of presynaptic neurons
• Dopamine exerts its effects on the
postsynaptic neuron through its
interaction with dopamine receptors
• Dopamine receptors
– D1 family – comprising D1 & D5
– D2 family – comprising D2, D3 & D4
Dunlop BW, Nemeroff CB. Arch Gen Psychiatry 2007;64:327-37.
25

26. Neuroanatomical circuits involved in depression
Dunlop BW, Nemeroff CB. Arch Gen Psychiatry 2007;64:327-37.
26

27. MDD: Data from neuroimaging studies
• Neuroimaging findings are not uniequivocal, but several studies support the
hypothesis that major depression is associated with a state of reduced DA
transmission, possibly reflected by a compensatory up-regulation of D2 receptors
• Early studies found elevated striatal D2 binding levels in depressed patients
• Elevated D2 receptor binding may reflect increased numbers of D2 receptors in
depression, an increase in affinity of the receptor for the ligand, or a decrease in
availability of synaptic DA (which competes with the radiolabeled ligand for D2
binding)
• In a positron emission tomography study assessing DA neuronal function by
measuring radioligand uptake in the striatum, depressed patients with
psychomotor retardation exhibited reduced striatal uptake of the radioligand
compared with anxious depressed inpatients and healthy volunteers. Another PET
study observed reduced dopamine transporter binding in depression
Dunlop BW, Nemeroff CB. Arch Gen Psychiatry 2007;64:327-37.
27

28. Dopaminergic neurotransmitter systems and possible
regions of MDD symptom generation
Loss of physical energy,
retardation
Pre-frontal Loss of
Striatum Cortex mental
energy/
fatigue
Substantia Nucleus
Nigra Accumbens
Ventral
Loss of
Tegmental
Area
Loss of interest
pleasure
Nutt D et al. J Psychopharmacol 2007;21:461-71.
28

29.
Dopamine transport activity: In vivo binding of
11
C-βCIT-FE in humans
Effect observed after treatment with bupropion HCl
150 mg every 12 hours
Baseline 3 hours
12 hours 24 hours
Normalized to cerebellum
Learned-Coughlin SM et al. Biol Psychiatry 2003;54:800-5.
29

30. International Consensus Statement on Major
Depressive Disorder (ICSMDD)
• Existing treatment guidelines have the following basic
principles in treating patients with MDD:
– Establish a correct diagnosis by using screening and diagnostic
tools along with a full clinical psychiatric assessment
– Assess the patient’s depression severity, current stressors,
comorbidities and suicide risk
– Select a treatment setting (inpatient vs outpatient) depending
on severity of depression
– Establish a therapeutic alliance and educate the patient and
family about depression and its treatment
– Choose appropriate individualized treatments of an adequate
dose and duration to help the patient achieve remission
Nutt DJ et al. J Clin Psychiatry 2010;71 [Suppl E1]:e08.
International Consensus Statement on Major Depressive Disorder (ICSMDD)
30

31. ICSMDD: Selecting treatments for depression
• Antidepressants are first-line therapy for moderate and
severe major depression:
– SSRIs, SNRIs, and NDRIs preferred due to tolerability
profiles
• SSRI (selective serotonin reuptake inhibitor)
• SNRI (serotonin-norepinephrine reuptake inhibitor)
• NDRI (norepinephrine-dopamine reuptake inhibitor)
• Consider psychotherapy as monotherapy for mild depression
and as adjunctive therapy for moderate or severe depression
• Benzodiazepine monotherapy should be avoided
• Treat to remission and monitor progress after remission
Nutt DJ et al. J Clin Psychiatry 2010;71 [Suppl E1]:e08.
International Consensus Statement on Major Depressive Disorder (ICSMDD)
31

32. Second-generation antidepressants in MDD
• No substantial difference in efficacy or effectiveness (meta-
analysis of 203 studies)1-2
• Response and remission rates generally similar between the
SSRIs and between the newer classes3-6
1.Gartlehner G et al. Ann Intern Med 2008;149:734-50; 2. Qaseem A et al. Ann Intern Med 2008;149:725-33;
3. Thase ME. Psychopharmacol Bull 2008;41:58-85; 4. Thase ME et al. J Clin Psych 2005;66:974-81;
5. Papakostas GI et al. J Psychopharmacol 2008;22:843-8; 6. Olver JS et al. CNS Drugs 2001;15:941-54.
32

34. ACP Review: Relative benefit of response
– SSRIs, SSNRIs, SNRIs & other 2nd-generation ADs
Gartlehner G et al. Ann Intern Med 2008;149:734-50.
ACP American College of Psychiatrists
34

35. Antidepressants – How to choose?
• Generally comparable overall efficacy for MDD
– No substantial difference in efficacy or effectiveness (meta-analysis of 203 studies) 1-2
– Response and remission rates generally similar between SSRIs and newer classes 3-6
• Second-generation antidepressants have better tolerability and safety than older
classes7
• Some may be better for specific symptom clusters or patient subpopulations 8
• Consider psychiatric and medical comorbidity
• Consider approved indications
• Consider differing tolerability profiles
– Poor tolerability can affect treatment adherence and, ultimately, patient outcomes
1.Gartlehner G et al. Ann Intern Med 2008;159:734-50; 2. Qaseem A et al. Ann Intern Med 2008;159:725-33;
3.Thase ME. Psychopharmacol Bull 2008;41:58-85; 4. Thase ME et al. J Clin Psych 2005;66:974-81;
5. Papakostas GI et al. J Psychopharmacol 2008;22:843-8.; 6. Olver JS et al. CNS Drugs 2001;15:941-54;
7. Nutt DJ et al. J Clin Psychiatry 2010;71 [Suppl E1]:e08; 8. Papakostas GI. J Clin Psychiatry 2010;71[suppl E1]:e03.
35

36. Hypothetical model: Differential actions of ADs on
symptoms of positive and negative affect
Depression with loss of
interest and energy
Loss of
positive Loss of
affect pleasure/enjoyment
Loss of
motivation and energy
Loss of
DA/NE agents
interest Low mood
Sadness Guilt
Depression
Irritability with anxiety
Fear
Anxiety
Negative affect
NE/5HT agents
Nutt D et al. J Psychopharmacol 2007;21:461-71.
Ads Anti- Depressants.
NE Norepinephrine/Serotonin Agents.
DA/NE Dopamine Norepinephrine Agents
36

37. Characteristics of depression
• MDD is associated with two mood states1-3:
1. Negative affect:
• broad range of negative mood states e.g. anxiety, irritability, hostility,
guilt and loneliness
• these mood states are associated with both depression and anxiety
disorders
2. Decreased positive affect
• loss of interest, loss of energy and loss of motivation
• In addition, anxiety disorders are often comorbid with MDD4
1. Nutt D et al. J Psychopharmacol 2007;21:461-71.
2. Watson D, Tellegen A. Psychol Bull. 1985; 98: 219-35
3. Shelton RC, Tomarken A.J Psych Serv 2001;52:1469-78.
4. Rapaport MH. J Clin Psychiatry 2001;62(Suppl 24):6-10
37

38. Remission: The goal of MDD treatment
• Partial remission:
– Some MDD symptoms still
present, but full diagnostic
criteria for MDD no longer
met
• Full remission:
– No significant symptoms of
depression American Psychiatric Association. DSM-IV-TR. Washington, DC: APA, 2000.
38

39. Relapse risk decreases the longer one is well
Remission Recovery
Relapse Recurrence
Normal mood
Pro
gres Relapse +
Symptoms
Severity
Response
sion
to
50% improvement
+
diso
rde
Depression
r
Acute Continuation Maintenance
Kupfer DJ. J Clin Psychiatry 1991;52(Suppl):28–34.
39

40. Key Issues in managing MDD and achieving remission
• MDD is a heterogeneous disorder: symptom profiles vary
widely among individuals and between episodes1,2
• Response to antidepressants is inconsistent and
unpredictable1,2
• Residual symptoms are common3,4
• Side-effects negatively impact compliance and long-term
outcome5,6
1. Belmaker RH,Agam G. N Engl J Med 2008;358:55−68; 2. Stahl SM et al. J Clin Psychiatry 2003;64(Suppl 14):6−17;
3. Nierenberg AA et al. J Clin Psychiatry 1999;60:221−225. 4. Nelson JC et al. J Clin Psychiatry 2005; 66:1409−14.
5. Zajecka JM. J Clin Psychiatry 2000;61(Suppl 2):20-5; 6. Lin EHB et al Medical Care 1995;33:67-74.
40

41. Antidepressant non-adherence and early drop out…
common problems
• Nearly one-third stop in the first month1
• About 44% no longer taking after 3 months2
• Early drop out:3
– 28% by week 4
– 43% by week 8
– 52% by week 12
1. Golden RN et al. J Clin Psychiatry 2002;63:577-84;
2. Lin EHB et al. Medical Care 1995;33:67-74;
3. Maddox JC et al. J Psychopharmacol 1994;8:48-53.
41

42. September 23, 2012 Ammoura
Ayman H. 42

43. Adverse events: A major cause of treatment
discontinuation
Poor early tolerability
High early drop out
• Reasons for outpatient non-adherence:
– Adverse events: 62–66% of patients cited adverse events as a major
cause of dropout
– Lack of education about what to expect from antidepressants
Lin EHB et al. Medical Care 1995;33:67-74; Maddox JC et al. J Psychopharmacol 1994;8:48-53.
43

44. Side effects of antidepressants
• All antidepressants carry some risk of side effects
• Side effects can include
– Nausea
– Sedation
– Insomnia
– Sexual dysfunction
– Weight gain
• There is potential for emergence or worsening of suicidal behaviour during
antidepressant therapy in patients aged <25 years
• Although risk of side effects may deter patients from accepting treatment, they
should be informed that risks of untreated depression probably outweigh risk of side
effects
• Choice of treatment should consider impact of possible AEs on individual patient
Nutt DJ et al. J Clin Psychiatry 2010;71 [Suppl E1]:e08
AEs Adverse Events
44 .

45. SSRI/SNRI associated nausea and rationale for
controlled-release SSRI/SNRI
• Gut mucosa enterochromaffin cells secrete 5-HT
• Rapid dissolution and absorption of SRIs leads to upper GI
high mucosal drug concentrations
• Nausea from 5-HT3 receptor stimulation in peripheral
duodenal synapses
• Optimizing rate and site of SRI absorption should minimize
the incidence and severity of nausea
Golden RN et al. J Clin Psychiatry 2002;63:577–84.
Serotonin receptors, also known as 5-HT (5-hydroxytryptamine receptors)
45

46. Side effects influencing psychiatrists’ choice of
antidepressant
25%
Choice of antidepressant should take into
20.3%
account:
17.7% -possible adverse events of different
20% treatments, and
- what would be important for the
individual patient
% of Patients
15%
9.4%
7.2%
10% 6.4%
4.2%
5%
0%
Sexual Weight Fatigue Anticholinergic Agitation Insomnia
Dysfunction Gain Effects
Zimmerman M et al. Am J Psychiatry 2004;161:1285-9.
46

47. Pharmacotherapies: SSRIs
• Better tolerated than tricyclic antidepressants1
• Citalopram 20–60mg/day
• Escitalopram 10–20mg/day • High safety in overdose1
• Fluoxetine 10–40mg/day • May cause insomnia, agitation, sedation, GI
distress and sexual dysfunction1
• Paroxetine 20–50mg/day
• • Increased risk of hyponatraemia; older age and
Sertraline 50–150mg/day1
female sex are risk factors2
• Interact with CYP-450 isoenzymes by inhibition2
• Can increase the anticoagulant effect of warfarin2
• Do not discontinue abruptly; taper the dose2
• Lower starting doses recommended in the
elderly2
• Paroxetine may be associated with
anti-cholinergic side effects2
1. Rush AR, Nierenberg AA. 2009. Chapter 13 In: Kaplan & Sadock's Comprehensive Textbook of Psychiatry.
US: Lippincott Williams & Wilkins;
US doses are listed. Please refer to local label 2. Sussman N. 2009. Chapter 31 In: Kaplan & Sadock's Comprehensive Textbook of Psychiatry. US:
recommendations for dosing in the elderly Lippincott Williams & Wilkins.
47

48. Pharmacotherapies: Tricyclics
 Desipramine 75–300mg/day  Potential for anti-cholinergic and sedative
effects2
 Nortriptyline 40–200mg/day1  Avoid in patients with a QTc interval of
450 msec or greater2
 May be fatal in overdose1, 2
 Potentially dangerous when given with the
MAOIs: fatal hypertensive reaction may occur
when a large dose of a tricyclic is given to a
patient already on an MAOI2
1. Rush AR, Nierenberg AA. 2009. Chapter 13 In: Kaplan & Sadock's Comprehensive Textbook of
Psychiatry. US: Lippincott Williams & Wilkins;
2. Nelson JC. 2009. Chapter 31 In: Kaplan & Sadock's Comprehensive Textbook of Psychiatry. US:
US doses are listed. Please refer to local label
Lippincott Williams & Wilkins.
recommendations for dosing in the elderly Monoamine oxidase inhibitors MAOI’s
48

49. Pharmacotherapies: SNRIs
 Duloxetine 60–120mg/day  Higher doses may cause hypertension
 Sleep changes and GI distress are common
 Venlafaxine 150–375mg/day
 Abrupt discontinuation may result in
discontinuation symptoms
US doses are listed. Please refer to local label Rush AR Nierenberg AA. 2009. Chapter 13 In: Kaplan & Sadock's Comprehensive Textbook of
Psychiatry. US: Lippincott Williams & Wilkins.
recommendations for dosing in the elderly
49

50. Pharmacotherapies: NDRIs
 Bupropion 200-400mg/day1  Dopamine Reuptake Inhibitor
 No sexual dysfunction or weight gain.
 Bupropion SR 300-400mg/day 2
 Bupropion XL 300-450mg/day3
1. Rush AR Nierenberg AA. 2009. Chapter 13 In: Kaplan & Sadock's Comprehensive Textbook of
US doses are listed. Please refer to local label Psychiatry. US: Lippincott Williams & Wilkins; 2. GSK.
recommendations for dosing in the elderly 3. BTA Pharmaceuticals, Inc. Wellbutrin XL prescribing information 2010.
50

51. Pharmacotherapies based on serotonin and
norepinephrine
Norepinephrine, 5HT2 and 5HT3  Sedation and weight gain are common with
mirtazapine3
antagonist
Mirtazapine 15–30mg/day1
Serotonin antagonist and reuptake
inhibitor
Nefazodone 300–600mg/day in
divided doses2
Trazodone 150–600mg/day1
1. Rush AR. Nierenberg AA. 2009. Chapter 13 In: Kaplan & Sadock's Comprehensive Textbook of
Psychiatry. US: Lippincott Williams & Wilkins;
2. Khan AA, Kornstein, SG. Chapter 31 In: Kaplan & Sadock's Comprehensive Textbook of Psychiatry.
US: Lippincott Williams & Wilkins
US doses are listed. Please refer to local label 3. Thase ME. Chapter 31 In: Kaplan & Sadock's Comprehensive Textbook of Psychiatry. US:
Lippincott Williams & Wilkins.
recommendations for dosing in the elderly
51

52. Pharmacotherapies: Stimulants
• Reports of use of dextroamphetamine and
methylphenidate for
– Depression secondary to medical conditions
– Apathy and depression secondary to CNS trauma
– Augmentation in some cases of treatment-resistant
depression
• Studies suggest modafinil may also be useful in
treatment-resistant patients for augmentation of
antidepressant therapy
Fawcett J. Chapter 31 In: Kaplan & Sadock's Comprehensive Textbook of Psychiatry. US: Lippincott Williams & Wilkins .
52

53. Anti-depressive efficacy in MDD with
anxiety symptoms
• Clinical guidelines based on evidence  A review of second-generation
from six head-to-head trials of antidepressants in 10 head-to-
second-generation antidepressants head trials found comparable
found similar antidepressive efficacies in the treatment of
efficacies for:1 anxiety associated with MDD for:
– Fluoxetine or paroxetine vs  Fluoxetine, paroxetine and
sertraline sertraline
– Sertraline vs bupropion  Sertraline and bupropion
– Sertraline vs venlafaxine  Sertraline and venlafaxine
• A pooled analysis of 10 studies  Citalopram and mirtazapine
analysis showed comparable efficacy
for bupropion and SSRIs in patients  Paroxetine and nefazodone
with MDD and low to moderate
levels of anxiety2
1. Qaseem A et al. Ann Intern Med 2008;149:725-33;
Qaseem A et al. Ann Intern Med 2008;149:725-33.
2. 2. Papakostas GI et al. J Clin Psychiatry 2008;69:1287–92.
53

54. Augmentation With Bupropion:
• Bupropion HCL Wellbutrin XL(BupropionHCL)combined
with SSRI’s is well tolerated and may be effective in treating depressed
patients who have an inadequate response to an SSRI 1
• Bupropion HCL augmentation facilitated treatment response in a
majority of non-responders to SSRI monotherapy
• Bupropion HCL with Escitalopram results in more rapid and
increased remission related to effects of Escitalopram used as mono
therapy3
1. Charles DeBattista et al. A prospective trial of Bupropion SR Augmentation of Partial and Non-Responders to Serotonergic Antidepressants, Journal
of Clinical Psychopharmacology, Volume 23, 2003; 27-30
2. T Eller et al. Effects of Bupropion augmentation on pro-inflammatory cytokines in Escitalopram-resistant patients with major depression disorder,
Journal of Psychopharmacology 2009 23; 854
3. Stewart w. et al. Does dual antidepressant therapy as initial treatment hasten and increases remission from depression? Journal of Psychiatric
Practice 2009: 15:337-345
47

55. Bupropion XL for depression with reduced energy,
pleasure and interest
• A prospective, double-blind, placebo-controlled study (n=274)
• Entry criterion based on Inventory of Depressive
Symptomatology (IDS) energy, pleasure, interest subset:
– Item 19 - general interest/involvement
– Item 20 - energy/fatigability
– Item 21 - pleasure/enjoyment
– Item 22 - sexual interest
– Item 30 - leaden paralysis/physical energy
– Entry: total score ≥7, minimum of 1 on ≥4/5 items
Some subjects received daily doses of bupropion XL > 300mg during the study
Jefferson JW et al. J Clin Psychiatry 2006;67:865-73.
55

57. Less residual sleepiness and fatigue following remission
with bupropion
Pooled analysis of 6 randomized controlled studies#
50 Bupropion (n=308)
SSRIs (n=324)
% of patients with residual
40
32.1
30.2
30
symptoms
* †
20.5 19.5 *p=0.0014 vs SSRIs
20 †
p=0.002 vs SSRIs
10
0
Residual Sleepiness Residual Fatigue
# Includes bupropion doses above the licensed dose for Europe and most non-
North American Countries
~52% of patients received doses of ≤300mg Papakostas GI et al. Biol Psychiatry 2006;60:1350-5.
57

58. Bupropion XL: Patient-rated depressive symptomatology vs
placebo
Primary endpoint: Mean IDS-IVR-30
*
*
*
*p<0.05 for difference between
bupropion and placebo
IDS-IVR-30 = 30-item Inventory of Depressive Symptomatology-
Self-Report, interactive voice response version Jefferson JW et al. J Clin Psychiatry 2006;67:865-73.
58

59. Conclusions
1. MDD constitutes a significant public health and social burden globally
2. It is often comorbid with other mental disorders, including anxiety
3. MDD is under-recognized and often under- and/or inappropriately
treated
4. As a heterogeneous disorder, response to antidepressants is
inconsistent and unpredictable and MDD is therefore under- and/or
inappropriately treated
5. A high proportion of patients with MDD experience diminished interest
or pleasure in their daily activities (anhedonia) – reduced dopaminergic
activity has been linked to this
6. Treatments should be individualized based on depressive
symptomatology
59

60. Mujtaba Nasar
60