Unipolar depression, also known as major depressive disorder, is characterized by at least two weeks of depressed mood or loss of interest accompanied by other cognitive and physical symptoms. It is a complex disorder that can manifest through emotional, physical, and cognitive symptoms due to involvement of many brain regions. Treatment goals include reducing symptoms, restoring function, and minimizing relapse risk. While SSRIs effectively treat emotional symptoms, dual-acting antidepressants that increase both serotonin and norepinephrine may better treat the full symptom spectrum due to the roles of these neurotransmitters in both the brain and spinal cord. Achieving full remission is important for improving long-term outcomes, as residual symptoms are associated with higher relapse risk.

1. Unipolar Depression
Dr. Lara Alqam
1st year resident in psychiatry

2. Major Depressive Disorder
 Mood disorder Had at least 2 weeks of a
major depressive episode which caused
significant distress or disability. Had no
history of mania or hypomania. This was not
due to a medical or substance use disorder.
Vincent Van 1890

3. Diagnostic Criteria
 A. Five (or more) of the following symptoms have been
present during the same 2-week period : (1) depressed
mood or (2) loss of interest or pleasure.
 1. Depressed mood most of the
 2. Markedly diminished interest or pleasure in all, or almost
all, activities most of the
 3. Significant weight loss when not dieting or weight gain
(e.g., a change of more than 5% of body weight in a month),
or decrease or increase in appetite nearly every day.
 4. Insomnia or hypersomnia.
 5. Psychomotor agitation or retardation
 6. Fatigue or loss of energy nearly every day.
 7. Feelings of worthlessness or excessive or inappropriate
guilt (which may be delusional)
 8. Diminished ability to think or concentrate.
 9. Recurrent thoughts of death (not just fear of dying),
recurrent suicidal ideation without a specific plan, or a
suicide attempt or a specific plan for committing suicide.

4.  B. The symptoms cause clinically significant distress or
impairment in social, occupational, or other important
areas of functioning.
 C. The episode is not attributable to the physiological
effects of a substance or to another medical condition.
 D. The occurrence of the major depressive episode is not
better explained by schizoaffective disorder, schizophrenia,
schizophreniform disorder, delusional disorder, or other
specified and unspecified schizophrenia spectrum and
other psychotic disorders.
 E. There has never been a manic episode or a hypomanic
episode.

5.  Approximately 10% of men and 20% of
women are affected
 Heritability: 25% (less severe depression)
to 50% (more severe depression)
 Depression is common, economically
burdensome, and can be a lifelong
disorder for some patients.
 Recurrence rates vary from 50% after 1
episode to 90% after 3 episodes of
depression.
The Epidemiology of Depression

6.  Nearly 75% of people who meet criteria for
depression, also meet criteria for another
psychiatric disorder (anxiety, substance-
use, impulse control)
 Most episodes of depression resolve
without treatment, however vast majority
of those who recover will experience
recurrences.
 Over 25% of patients will suffer from
chronic depression

7. Increasing Importance of
Depression
 MDD is among the most costly diseases in the world,
and it is becoming more prevalent.
 DALYs=disability-adjusted life years.
 DALYs for a disease are the sum of the years of life
lost due to premature mortality (YLL) in the population
and the years lost due to disability (YLD) for incident
cases of the health condition
 In 2000, MDD was the number 4 cause of DALYs
among 15-44 year olds.
 MDD is estimated to be the number 2 cause of Years
Lived with Disabilities (YLDs) in 2020.

8. The Socioeconomic Burden of
Depression
 Significantly more people with sub--
syndromal depressive symptoms or major
depression reported impairment in eight of
10 functional domains than did subjects with
no disorder

9. Multiple Core and Associated
Symptoms in MDD
 To establish that depression is a complex disorder
that can manifest through a variety of emotional,
physical, cognitive, and other associated symptoms
(e.g., anxiety, worry, and pain).
 Note that the complexity of symptom presentation
can lead to depression being a difficult condition to
diagnose.
 The variety of symptoms of depression suggests
that many areas of the brain and neural networks
may be involved in depression.

10.  Amygdala - controls autonomic responses associated with fear,arousal,
formation of memories of emotional events
 Changes in amygdala volume and activity observed in depressed
patients.
 Most consistent change: increased amygdala activity
 Prefrontal cortex (PFC) –Executive function of the brain: discrimination
between conflicting, thoughts, planning complex, cognitive behaviors,
working toward goal, personality expression , etc.
 One of PFC functions is to inhibit the activity of amygdala to allow
focus on tasks
 fMRI and PET show decreased PFC activity in depressed vs. healthy
 individuals
 Hippocampus : Depressed patients exhibit memory loss (orientation,
text
 recall tests)
 • The underlying cause is thought to be decrease in the functionality
and the volume of hippocampus
 • Hippocampus is responsible for spatial orientation and long-term
memory
Regions of brain involved in depression

11. Persistent Depressive Disorder
(Dysthymia) vs. MDD
 persistent depressive disorder
(dysthymia) is a depressed mood that
occurs for most of the day, for more
days than not, for at least 2 years, or
at least 1 year for children and
adolescents.

12. Depression:
Treatment Goals
 Once depressive disorders are
diagnosed, the initial objectives of
treatment, in order of priority, are to
– Reduce and ultimately remove all signs
and symptoms of the depressive disorder
– Restore occupational and psychosocial
roles/functions to the asymptomatic state
– Minimize the risk of relapse and
recurrence

13. Residual Depressive Symptoms are
Associated with Greater Risk of
Relapse
 Presence of residual symptoms of
depression was associated with a relapse
rate of 76% compared with a relapse rate
of 25% among patients who did not have
residual symptoms
 In this study Patients with residual
symptoms relapsed almost 3 times faster
(median 68 weeks vs. 23 weeks)
compared with asymptomatic patients

14. Many Residual Symptoms are
Physical
 Many Residual Symptoms are Physical
 With current antidepressant treatment,
residual symptoms are often physical
symptoms.

15. Depression:
Response vs. Remission
 Epidemiologic and clinical data support the goal of
treating depressed patients to wellness or full
remission. Many patients improve but fail to achieve
full remission with antidepressant treatment and
continue to have residual symptoms, which cause
distress and dysfunction.
 These residual symptoms may meet criteria for sub-
syndromal and minor depression. Patients who
have these milder syndromes after treatment have
a greater risk of relapse and recurrence than do
those who remain symptom-free.


16. Depression:
Response vs. Remission
 The HAMD17 has 17 items and the
scores go up to 52.
 The typical depressed patient in
primary care tends to have HAMD
between 15 and 19
 The typical Psychiatric outpatient
tends to have HAMD between 20 and
high 20s.

17. Multiple Core and Associated
Symptoms in MDD
– To establish that depression is a complex
disorder that can manifest through a variety of
emotional, physical, cognitive, and other
associated symptoms (e.g., anxiety, worry, and
pain).
– Note that the complexity of symptom
presentation can lead to depression being a
difficult condition to diagnose.
– The variety of symptoms of depression suggests
that many areas of the brain and neural
networks may be involved in depression.

18. 5-HT(hydroxytryptamine) and NE:
The Role in Both the Brain and Spinal
Cord
 Serotonin has been implicated in depression
through its brain pathways, starting in the Raphe
nuclei and projecting up to the prefrontal cortex
and limbic system.
 Norepinephrine has been similarly implicated, with
its brain pathways starting in the Locus Ceruleus
and projecting up to the same regions in the
prefrontal cortex and limbic system.
 However, there are also downward projections of
these serotonin and norepinephrine pathways from
their brainstem nuclei into the spinal cord, and
these pathways also have implications for the
symptoms and treatment of depression.

19. 5-HT and NE:
The Role in Both the Brain and
Spinal Cord
 Antidepressants that effect either serotonin
or norepinephrine specifically are effective
agents.
 But while serotonin and norepinephrine do
mediate a broad range of depressive
symptoms, they do have distinguishable
profiles in mediating symptoms.
 Therefore, dual-acting agents may provide
benefits in treating the full range of
depressive symptoms, both emotional and
physical.

20. 5-HT and NE at the Synaptic
Level: Healthy vs. Depressed
 The depressed person has a relative
reduction in the amount of serotonin
and norepinephrine available in the
synaptic cleft

21. Neurotransmitter Depletion
Studies

22. Neurotransmitter Depletion Studies:
A Schematic View

23. TCAs at the Synaptic
Level
 While TCAs may bind to and block the
serotonin and norepinephrine transporter,
(their proposed mechanism of action), they
also bind to the adrenergic, histaminic and
cholinergic receptors within their
recommended dose range.
 Adrenergic blockade can cause orthostatic
hypotension, histamine blockade can cause
sedation and weight gain, and cholinergic
blockade can cause dry mouth, urinary
retention, constipation, and tachycardias.

24. TCAs; advantages and
disadvantages
 TCAs have the advantage of greater efficacy in
depression through their dual mechanism of action.
 They also have proven efficacy in pain symptoms,
as well as in treating chronic pain syndromes.
 Unfortunately their use is limited by side-effects
produced through the need to titrate to higher
doses and their poor receptor site selectivity.
 Orthostatic hypotension, anticholinergic and
antihistaminic side-effects can occur at the starting
doses.
 Tricyclic antidepressants are cardiotoxic in overdose
through their inhibition of sodium fast channels.

25. SSRIs Enhance 5-HT at the
Synaptic Level
 SSRIs increase the amount of
serotonin available in the synapse, but
do not effect the levels of
norepinephrine

26. SSRIs; advantages and
disadvantages

27. SNRIs Enhance Both 5-HT
and NE at the Synaptic Level
 By blocking both the serotonin and
norepinephrine reuptake transporter,
SNRIs increase the amount of both
neurotransmitters available in the
synapse.

28. SNRIs; advantages and
disadvantages

29. Depression:
Reduced Activity from Descending 5-HT
and NE Pathways
 5-HT and NE are the
neurotransmitters in the descending
inhibitory pain pathway.
 If depression has caused a decrease in
these neurotransmitters, then there
would be a decrease in the pain
inhibition mediated by this spinal
pathway, leading to increased pain
perception.

30. The Role of 5-HT and NE in
Painful Somatic Symptoms
 NE and 5-HT neural circuits directly
modulate the descending pathways
and compose an integral part of the
complex system that controls
pain perception

31. The Role of 5-HT and NE in
Pain Perception
 5-HT and NE contribute to the
centrally-mediated emotional and
sensory response to pain.
 They also mediate pain perception
through the descending modulatory
pain pathway, which inhibits the
ascending signal.

32. Neurotransmitter Pathway
Story:
It’s Not All in Your Head
 Why the dual action (serotonin
and norepinephrine) agents to
treat aches and pains?
– 5-HT and NE are instrumental in the
treatment of depression and pain.
– 5-HT and NE modify the effects of
substance P, GLU, GABA and other pain
mediators

33. Physical Symptoms are Not
Adequately Addressed by
SSRIs
 While SSRIs were effective in treating
core emotional symptoms of MDD,
they were not very effective in treating
the physical symptoms of depression.
 This prospective open-label study with
various SSRIs further validates the
hypothesis that single–action agents
are not that effective for treating the
full spectrum of depressive illness.

37. Ten Leading Causes of
Disability in the World
Type of Disability Cost (in
DALYs)
Cumulative
%
of Cost
Unipolar major depression 42,972 10.3
Tuberculosis 19,673 14.9
Road traffic accidents 19,625 19.6
Alcohol use 14,848 23.2
Self-inflicted injuries 14,645 26.7
Bipolar Disorder 13,189 29.8
War 13,134 32.9
Violence 12,955 36.0
Schizophrenia 12,542 39.0
Iron deficiency anemia 12,511 42.0

38. Antidepressants - History
 1958 Monoamine oxidase inhibitors (MAOIs)
 1958 Tricyclics (TCA’s)
 1982 Trazodone (Deseryl)
 1988 Fluoxetine (Prozac)
 1989 Bupropion (Wellbutrin)
 1994 Nefazodone (Serzone)
 1994 Venlafaxine (Effexor)
 1996 Mirtazapine (Remeron)

39. Treatment Response
Categories
STATE OBJECTIVE
CRITERION
CLINICAL
STATUS
PREVALENCE
IN RCTS
Remission HAM-D ≤ 7 No residual
psychopathology
~ 40%
Response ≥ 50% decrease
in HAM-D
without
remission
Substantially
improved, but with
residual sxs
~ 25%
Partial
response
25%-50%
decrease in HAM-
D
Mild-moderate
improvement
~ 10%
Nonresponse < 25% decrease
in HAM-D
No clinically
meaningful response
~ 25%

40. Efficacy vs
Effectiveness

41. Fig. 1. Survival analysis of weeks to major depressive episode relapse (MDE):
comparing patients with unipolar major depressive disorder who recovered from
intake MDE with residual subsyndromal depressive symptoms vs.
asymptomatic status. Wilcoxon Chi Square Test of Difference=47.96; P<0.0001.

42. Why Is Achieving Remission
Important?
 Residual symptoms put patients at high risk of
relapse and recurrence
– Patients with residual symptoms after
medication treatment are 3.5 times more likely
to relapse compared to those fully recovered
(Judd et al, 1998)
– This risk is greater than the risk associated
with having ≥ 3 prior depressive episodes
– Similar finding exists after response to
cognitive therapy

43. Subtypes of Depression
•Atypical
Reverse neurovegetative
symptoms
Mood reactivity
Hypersensitivity to rejection
MAO-I’s and SSRI’s are more
effective treatments

44. Subtypes of Depression
Psychotic (~10% of all MDD)
•Delusions common, may have
hallucinations
•Delusions usually mood
congruent
•Combined antidepressant and
antipsychotic therapy or ECT is
necessary

45. Subtypes of Depression
Melancholic
•No mood reactivity
•Anhedonia
•Prominent neurovegetative
disturbance
•More likely to respond to
biological treatments

46. Subtypes of Depression
Catatonic
•Motoric immobility (catalepsy)
•Mutism
•Ecolalia or echopraxia

47. What is the course of
antidepressant
response?

48. Why a temporal delay for
maximal therapeutic
benefit
 -adrenergic receptor down-
regulation
 5-HT2 receptor down-regulation

49. Tricyclic Antidepressants
(TCAs)
 Characteristic three-ring nucleus
 Clinical effects
 Normalization of mood and resolution of
neurovegetative symptoms
 Biochemical effects
 Inhibit monoamine uptake at nerve terminals
 May potentiate action of drugs that cause
neurotransmitter release
 Temporal delay of weeks for clinical effects,
although biochemical effects are immediate

50. Mechanism of action of
TCAs
“Tertiary” TCAs  Inhibit 5-HT uptake
imipramine (weaker inhibition of NE uptake)
amitriptyline
clomipramine
“Secondary” TCAs  Inhibit NE uptake
desipramine (weaker inhibition of 5-HT uptake)
nortriptyline

51. TCA Metabolism
N
CH3
H3C
N
N
CH3
H3C
N
N
CH3
H
N
CH3
H
nortriptyline
imipramine
amitriptyline
desipramine
tertiary amines secondary amines

52. In vivo action of TCAs
If one administers a tertiary TCA  there is always both the tertiary
and the secondary amine in the
circulation
If one administers a secondary TCA  there is only the secondary
amine in the circulation.

53. Neuropharmacology of
TCAs
 Inhibit monoamine uptake (NE and 5-
HT)
 Muscarinic cholinergic antagonism
 H1 histamine antagonism
 1-adrenergic antagonism

54. Tricyclics-
Contraindications
 QTc greater than 450 msec
 Conditions worsened by muscarinic
blockade (eg myasthenia gravis, BPH)
 pre-existing orthostatic hypotension
 Seizure disorder

55. Side effect profile of TCAs
 Dry mouth
 Constipation
 Dizziness
 Tachycardia
 Urinary retention
 Impaired sexual funtion
 Orthostatic hypotension

56. Low therapeutic index of
TCAs
 Cardiotoxicity: resulting from combination of:
 Conduction defects, arrhythmias
 Delirium
Potentiation of effects of other sedating drugs
 Consequences
 suicide
 requires care in prescribing
 monitoring drugs that might have synergistic
effects on monoamine function

57. Monoamine Oxidase
Inhibitors (MAOIs)
 Irreversibly inhibit monoamine
oxidase enzymes
 Effective for major depression,
panic disorder, social phobia
 Drug interactions and dietary
restrictions limit use

58. Biochemistry of MAO
 Occurs as two isoenzymes
 MAO-A –
• Oxidizes norepinephrine,
serotonin, tyramine
 MAO-B
selective for dopamine
metabolism

59. Dietary and Drug
Interactions
 Increased stores of catecholamines sensitize patients
to effects of sympathomimetics
 Accumulation of tyramine (sympathomimetic) = high
risk of hypertensive reactions to dietary tyramine
 requires dietary restrictions
 Interactions with other sympathomimetic drugs
 Antidepressants
 OTC cold remedies
• phenylpropanolamine
 Meperidine
 L-dopa

60. Examples of MAOIs
 Irreversible, non-selective MAOIs
 phenelzine
 isocarboxazid
 tranylcypromine
 Selective MAO-B inhibitors
 deprenyl (selegiline)
 loses its specificity for MAO-B in antidepressant doses
 Reversible monoamine oxidase inhibitors
(RIMAs)
 Moclobemide – not approved
 Appears to be relatively free of food/drug interactions

61. Serotonin syndrome
 Evoked by interaction between serotonergic agents
 e.g., SSRIs and MAOIs
 Combination of increased stores plus inhibition
of reuptake after release
 Symptoms
 Hyperthermia
 Muscle rigidity
 Myoclonus
 Rapid changes in mental status and vital signs
 Can be lethal

62. Selective Serotonin
Uptake Inhibitors
(SSRIs)
 Currently marketed medications
 fluoxetine (Prozac).
 sertraline (Zoloft).
 paroxetine (Paxil)
 fluvoxamine (Luvox)
 citalopram (Celexa)
 escitalopram (Lexapro)
 Selectively inhibit 5-HT (not NE) uptake
 Differ from TCAs by having little affinity for muscarinic,
as well as many other neuroreceptors

63. Selective Serotonin
Uptake Inhibitors
(SSRIs)
 Much higher therapeutic index than TCAs
or MAO-I’s
 Much better tolerated in early therapy
 Equal or almost equal in efficacy to TCAs

64. Side effects associated
with SSRIs
 Nausea
 Sexual dysfunction
 Delayed ejaculation/anorgasmia
 Anxiety
 Insomnia

65. Selective Norepinephrine-
Serotonin Reuptake Inhibitors
 Venlafaxine (Effexor) Duloxetine
(Cymbalta):
 relatively devoid of antihistaminergic,
anticholinergic, and antiadrenergic
properties
 nonselective inhibitor of both NE and 5-
HT uptake.
Adverse effects: GI , Sexual dysfunction,
hypertension (venlafaxine)

66. Other antidepressants
 Trazodone
mixed 5-HT agonist/antagonist
• 1 antagonist
• H1 antagonist
 Nefazodone (Serzone)
 5 HT2 antagonist
 Bupropion (Wellbutrin; Zyban)
 Inhibits uptake of DA and NE
 antismoking properties probably involves parent
molecule
 Lacks sexual side effects
 Seizure risk

67.  Mirtazapine (Remeron)
 2 antagonist
 5H2 and 5HT3 antagonist
 Net effect selective increase in
5HT1A function
 H1 antagonist
advantages: sedation, no adverse
sexual effects

68. Antidepressants and drug
interactions
 Pharmacodynamic
– Additive effects with alcohol and other sedating drugs
– MAOI interactions
 Pharmakokinetic
– Cytochrome P450-2D6 inhibition
 Fluoxetine and paroxetine
 Increased levels of TCAs, antipsychotics, warfarin
– Cytochrome P450-3A4 inhibition
 Nefazodone and fluvoxamine
 Increased levels of terfenadine, astemizole, cisapride –
can cause fatal arrhythmias

69. Other uses for antidepressants
 Panic Disorder
 Obsessive Compulsive Disorder
 Only the ADs that inhibit serotonin
reuptake
 Social Phobia
 Post Traumatic Stress Disorder
 Premenstrual Dysphoric Disorder
 Chronic pain syndromes

70. Treatment
Course
 One episode – 50% chance of
reoccurence
 Two episodes – 70% chance of
reoccurence
 Three or more episodes - >90%
chance of reoccurence

71. When Do You Characterize
a Response As Treatment
Resistant?
 After a patient has been on an antidepressant at for a
reasonable amount of time at an adequate dose
 No commonly accepted time point
– Most drug trial data comes from 8 week long studies
– If no onset of response by weeks 4 or 6, there is a 73-
88% chance of not having onset of response by end of
8 wk trial (Nierenberg et al, 2000), so 4 weeks is a
reasonable point to increase dose
– An 8-12 week course is consistent with acute
treatment framework and allows patients 8 weeks at a
dose expected to produce response