2. 1) Introduction
2) Classification
3) Etiology

3.  The fundamental disturbance is a change in mood
or affect. It can be depression or elation.
 Start at early age.
 Hard to diagnose in youth.
 Confused with normal teenage behavior, drug use
or other psychiatric illnesses.
 Tend to be recurrent and onset of individual
episodes is often related to stressful situations.
 High suicide risk.

4.  F30-F39
 F30- Manic episode
 F31- Bipolar affective disorder
 F32- Depressive episode
 F33- Recurrent Depressive disorder
 F34- Persistent mood(affective) disorder
34.0- Cyclothymia
34.1- Dysthymia
 F38- Other mood disorders
 F39- Unspecified mood disorders

5.  No single etiological factor
 Multifactorial etiology
 Muchmore data available for etiology of
Depression than of Mania.

6. Biological Psychological
•Family and •Stressful life events
genetics •Personality factors
•Neurotransmitters •Cognitive factors
•Neuro-endocrine •Psychodynamic
system Mood factors
•Immune system Disorder
•Sleep
Social
dysfunction
•Support system
(social support)

7. Integrative model of Etiology
Biological
Factors
Psycho-
logical Mood
Factors Vulnerability Disorder
Social
Factors

9.  Overall genetics has a greater role in Bipolar disorders (than
in unipolar)
1) FAMILY FACTOR –
 Risk of mood disorder is increased in first degree relatives of
both bipolar and unipolar probands.(bipolar>unipolar)
BIPOLAR DISORDER UNIPOLAR DISORDER
LIFE TIME RISK About 1% 10-20%
SEX RATIO 1:1 1:2
IN FIRST DEGREE
RELATIVES:-
LIFETIME RISK FOR BAD About 10% About 20%
LIFETIME RISK FOR 20-30% 20-30%
UNIPOLAR DISORDER
AVERAGE AGE OF 21 yrs 27 yrs
ONSET

10. 2) TWIN STUDIES-
 Concordance rates- monozygotics>dizygotics
bipolar>unipolar proband
BIPOLAR 1 DISORDER MAJOR DEPRESSIVE
DISORDER
MZ TWINS (60-70%) 50%
DZ TWINS (20%) (20%)
 The concordance rate for MZ twins is not 100%.
This indicates that non-heritable environmental
factors also play a significant role in mood disorder.

11. 3) ADOPTION STUDIES-
 These studies have shown that the biological
children of affected parent remain at increased risk
of mood disorder even if they are reared in non
affected adoptive family.
 Though studies showed varied results but a large
study showed-
3 fold increase in bipolar &
2fold increase in unipolar disorders
in the biological relatives of bipolar
probands!

12. 4) LINKAGE STUDIES-
 Chromosomes 18q & 22q – carry strong evidence
for linkage to bipolar disorder.
 CREB1 locus(locus for cAMP Response Element
Binding protein) on chr.2 – carry strong linkage
to unipolar disorder.
 All these facts show a strong genetic
association of mood dis ( BIPOLAR > UNIPOLAR)

14.  NT Deficient in Depression-
1. Serotonin
2. Norepinephrine
3. Dopamine
4. Gamma-aminobutyric acid (GABA)
5. Brain-derived neurotrophic factor (BDNF)
6. Somatostatin
 NT excess en Depression-
1. Acetylcholine
2. Corticotrophin Releasing Hormone (CRH)

15.  The 3 principle NTs involved in mood disorders are:-
-Norepinephrine
-Serotonin
-Dopamine
 These monoamines work in concert i.e.action of one is
influenced by other.
 E.g. NE can stimulate as well as inhibit release of 5HT.
Also, 5HT (at 5HT2A or 5HT2C) inhibits the release
of NE as well as DA.
5HT DA
NE 5HT
5HT NE

16. Norepinephrine regulation of serotonin.
Norepinephrine regulates serotonin release. It does this
by acting as a brake on serotonin release at alpha 2 receptors on axon
terminals and as an accelerator of
serotonin release at alpha 1 receptors at the somatodendritic area.

17. Norepinephrine as a brake on serotonin release

18. Norepinephrine as an accelerator of serotonin release

19. 5HT2A receptors regulate norepinephrine and dopamine.
Serotonin (5HT) regulates release of (NE) and (DA) in the prefrontal cortex via 5HT2A receptors located at the
somatodendritic ends of NE, DA, and gamma-aminobutyric acid (GABA) neurons.
Binding of 5HT at 5HT2A receptors on some NE and DA neurons in the brainstem directly inhibits release of
these neurotransmitters into the prefrontal cortex.
In addition, binding of 5HT at 5HT2A receptors on some GABA interneurons in the
brainstem increases GABA release, which then inhibits NE and DA release.

20. 5HT2C receptors regulate norepinephrine and dopamine.
(5HT) also regulates release of (NE) and (DA) in the prefrontal cortex via 5HT2C receptors
located on (GABA) interneurons in the brainstem.
Binding of 5HT at 5HT2C receptors on these GABA interneurons increases GABA release, which
then inhibits NE and DA release from their respective neurons

22.  Seems hyperactive. But since there are fewer
noradrenergic neurons, this can lead to a deficiency.
 Adverse childhood experiences can produce an over-
active responsiveness in this system that persists
into adulthood.
In situations that most people may not find too
stressful, the vulnerable depressed individual does
feels very stressed and may deplete NE-
Depression
 Depletion of NE with AMPT causes depression in
recovered/vulnerable patients but not normals.

23.  Plasma Tryptophan levels are decreased in untreated
depressed pts.
 CSF concentrations of 5HIAA is decreased in some
depressed pts. (but more in pts with impulse control
problem, suicidal tendency)
 Serotonin Function is Abnormal Between and During
Episodes of Major Depression.
-May explain why 80% of patients have recurrences of
major depressive episodes.
-May explain why prevention of relapse back into an
episode requires ongoing medication.

24.  Dopamine activity may be-
- reduced in depression &
- increased in mania.
 Drugs(eg Reserpine) & disease(eg.Parkinson dis)that
reduce Dopamine concentration are associated with
depressive symptoms.
 CSF shows low homovanillic acid (HVA).
 Depletion of dopamine with AMPT causes depression in
recovered patients but not in normals.

25.  Acetylcholine-
 Cholinergic neurons have interactions with all three
monoamine systems.
 Agonist can produce lethargy, anergia and psychomotor
retardation in normal subjects.
-can exacerbate symptoms in depression
-can reduce symptoms in mania.
 GABA-
 Has an inhibitory effect on ascending monoamine
pathways.
 CSF levels of GABA are reduced in depression.

26. Classic monoamine hypothesis of depression, part 1.
According to the classic monoamine hypothesis of depression, when there is a "normal" amount
of monoamine neurotransmitter activity, there is no
depression present.

27. Classic monoamine hypothesis of depression, part 2.
The monoamine hypothesis of depression posits that if the "normal" amount of
monoamine neurotransmitter activity becomes reduced,
depleted, or dysfunctional for some reason, depression may ensue.

28. Monoamine receptor hypothesis of depression.
The monoamine receptor hypothesis of depression extends the classic monoamine hypothesis of
depression, positing that deficient activity of monoamine neurotransmitters causes
upregulation of postsynaptic monoamine neurotransmitter receptors, and that this leadsto
depression.

29.  Despite all above discussion there is no clear and
convincing evidence that monoamine deficiency
accounts for depression; that is, there is no "real"
monoamine deficit.
 Likewise, there is no clear and convincing evidence that
abnormalities in monoamine receptors account for
depression.
 Emphasis is now turning to the possibility that in
depression there may be a deficiency in downstream
signal transduction distal to the receptor & the
related gene expression.

30.  Responsible for functioning & survival of CNS neurons.
 BDNF expression is decreased in stress & increased by
antidepressant medications.
 Under stress the gene for BDNF is repressed
Atrophy of vulnerable neurons in hippocampus
Depression
 This also explains consequences of repeated episodes
i.e. more and more episodes and less and less response
to treatment.
 Supported by imaging studies showing decreased brain
volume of related structures in depression.

31.  Suggests neuronal injury through a mechanism involving
electrophysiological kindling & behavioural sensitisation.
 Repeated exposure to stress and/or neurochemical
changes during depressed episode sensitize brain regions
responsible for affect
 Repeated episodes may permanently alter systems
within the CNS
 Leads to shorter well periods, increased frequency and
severity of illness
 Anticonvulsants like valproic acid & carbamazepine act
against this kindling process and prevent recurrences.

33. DSM-IV symptoms of depression.

34.  Each of these symptoms can be mapped onto
brain circuits that theoretically mediate these
symptoms,
 Also the hypothetical trimonoaminergic
regulation of each of these brain areas can
also be mapped.
 Then targeting each region with drugs that act
on the relevant NT can lead to reduction of
each individual symptom.

35. Matching depression symptoms to circuits
Functionality in each brain region is hypotheticaily associated with a different constellation of
symptoms. PFC, prefrontal cortex; BF, basal forebrain; S, striatum; NA, nucleus accumbens; T,
thalamus; HY, hypothalamus; A, amygdala; H, hippocampus; NT, brainstem neurotransmitter
centers; SC, spinal cord; C,cerebellum.

36.  Apart from mapping each symptom to specific area and
specific NT,, Many mood symptoms of depression can also
be categorised as having too little positive affect OR too
much negative affect.
 This idea is based on the fact that there are diffuse
anatomic connections of the trimonoaminergic
neurotransmitter system throughout the brain, with
1. Reduction of positive affect mainly due to diffuse DA
reduction
2. Increase in negative affect mainly due to diffuse 5HT
reduction
3. And NE dysfunction being involved in both..!!
Thus enhancing DA (and NE) function may theoretically
improve the reduced positive affect
&
Enhancing 5HT (and NE) function may improve the
increased negative affect..!!

44. DSM-IV symptoms of mania.

45. Matching mania symptoms to circuits.
Functionality in each brain region may be associated with a different constellation of symptoms.
PFC, prefrontal cortex; BF, basal forebrain; S, striatum; NA, nucleus accumbens; T, thalamus;
HY, hypothalamus; A, amygdala;
H, hippocampus; NT, brainstem neurotransmitter centers; SC, spinal cord; C, cerebellum

47. Note:-
Risk taking,
Grandiosity,
Pressured speech
Flight of Ideas,
(poor impulse control)
Racing thoughts
Due to hyperactivitiy
Are due to hyperactivity
In OFC,DLPFC,VMPFC
In the nucleus
accumbens
Regulated by 5HT, DA
& NE
Regulated by 5HT & DA

48. (Cognitive symptoms)

50. (Emotional
Symp)
(Cognitive
Symp)

53.  Depression has been associated with dysfunction of
the endocrine system, specifically:
1. Elevated levels of the stress hormone Cortisol
(Elevated HPA axis activity)
2. Malfunctioning of the Thyroid gland
3. Dysregulation of the release of Growth hormones

54.  Elevated HPA activity is a hallmark of mammalian stress
responses and one of the clearest links between depression
and biology of chronic stress.
 50% of depressed patients have elevated cortisol level
(resolves with treatment--- persistently increased level
indicate a high risk of relapse )
 CRH levels are also elevated in CSF of depressed pts.
(Central CRH receptor antagonists-possible antidepressants)
 Elevated HPA activity in depression has been documented via
Dexamethasone Suppression Test.
Nonsuppresion may implicate a loss of inhibitory
hippocampal glucocorticoid receptors resulting in increased
CRH drive.

55. Adverse childhood experiences
HPA axis function
Current Stress
CORTISOL
Decreased Decreased
Genetlic factors NA function 5HT function
Prefrontal cortex
Hippocampus
Past Depressive
episode Depressive syndrome

56.  Disturbed in about 5 to 10% of persons with depression
 About 1/3rd of pts have blunted TSH response to iv TRH.
 10% of pts may have circulating antithyroid antibodies.
 Does not usually normalize with effective treatment.
 Major therapeutic implication of a blunted TSH response
is evidence of an increased risk of relapse despite
preventive antidepressant therapy
 Some depressed patients benefit from Levothyronine
(T3).

57.  GH secretion stimulated by NE & DA
inhibited by somatostatin & CRH(from
hypothalamus)
 CSF somatostatin levels- decreased in depression,
and increased in mania.

58. 1. Lowered proliferative responses of lymphocytes to
mitogens.
2. Lowered natural killer cell activity.
3. Increase in positive acute phase proteins.
4. Increase in cytokine levels(eg-IL1,IL6)
 Cytokines are known to provoke HPA axis activity–-
dysfunction of HPA axis
 Cytokines can induce „tryptophan
oxygenase‟(tryptophan metabolizing enzyme)----
lowering tryptophan levels-- vulnerability for
depression.

59.  Initial and terminal insomnia
 Multiple awakenings & In depression
 Apparent Hypersomnia
 Decreased need for sleep- in mania
 Common abnormalities:-
 Reduced REM latency
 A longer first REM period and increased REM density.
 Frequent awakenings and arousals
 Difficulty in falling asleep decreased total sleep time
 Decreased REM latency may persist in recovered depressed pts
and indicate a vulnerability to relapse
 Thought exact mechanism not known but abnormalities in REM
sleep in depressed pt may be attributed to excessive
sensitivity of Cholinergic receptors

60. Biological
Family and genetics
Neurotransmitters
Neuro-endocrine
system
Immune system
Sleep dysfunction

62.  Stressful events strongly linked to onset of mood disorders.
 Context and meaning of the stressor more important than the exact
nature of event(i.e. a stressor which has more negative impact on pt‟s
own self esteem is more likely to produce depression)
 Stressful events more often linked with initial episodes than with later
episodes.
eg. Loss of parent before age 11,
loss of spouse, unemployement etc.
 A theory proposed said that-
Stress accompanying 1st episode
long lasting changes in brain‟s biology
(NT imbalances, loss of neurons etc)
High risk for developing subsequent episode of mood disorder(even
without external stressor)

63.  Person with certain personality disorder- obsessive
compulsive, histrionic & borderline may be at greater risk
for depression.
 Sociotropy (i.e. a high need for approval) is associated
with increased risk for depression.
 Learned Helplessness:
 Seligman‟s experiments with rats and dogs
 Learned helplessness in humans linked with attributions
of a lack of control after experiences of being in an
impotent position
 Environment which lacks positive reinforcement >
reduction in activities and withdrawal
 Positive reinforcement for the depressed role.

64.  Depression rooted in an early defect in the attachment
relationship with the caregiver(eg. Disturbance in the
infant-mother relationship during the oral phase increases
vulnerability to depression). Often the loss or threatened
loss of a parent.
 Adult relationships unconsciously constructed in a way
that reflects this loss e.g. Loss of early attachment >
dependence or avoidance in current relationships.
 Any present event involving loss reactivates the primal
loss and the person regresses to the childhood trauma >
depression

65.  Psychodynamic factors in Mania-
 Most theories view manic episodes as a defense
against underlying depression
(like inability to tolerate a tragedy such as loss of a
parent)
 Manic state may also result from a tyrannical
superego which produces intolerable self
criticism that is then replaced by euphoric
self-satisfaction.

66.  According to cognitive theory, depression results from
specific cognitive distortions(illogical ways of thinking)
present in persons prone to depression.
 Depressed pt characteristically have recurrent negative
thoughts (c/a Automatic thoughts)
(Aaron Beck’s cognitive triad of depression- ie negative
views about the self, environment,& future)
 These automatic thoughts persists bcoz of illogical ways
of thinking (c/a Cognitive distortions)
 Depression also predisposed by „dysfunctional beliefs‟
(eg. „if I am not perfectly successful I am nobody‟)

67. Early life experiences
Formation of dysfunctional beliefs
Critical events
Beliefs activated
Negative Automatic thoughts
Symptoms of Depression
(Behavioral, motivational, affective,
cognitive, somatic)
COGNITIVE MODEL OF DEPRESSION

68. Psychological
Stressful life events
Personality factors
Psychodynamic
factors
Cognitive factors

70.  High levels of social support are linked to a
decreased occurrence of mood disorders and also an
increase in the speed of recovery
 Brown & Harris 1978:
 Two groups of woman who had experienced a serious
life stress
 Those who had a close friend > 10% became depressed
 Those who did not have a supportive relationship > 37%
became depressed

71. Biological Psychological
•Family and •Stressful life events
genetics •Personality factors
•Neurotransmitters •Cognitive factors
•Neuro-endocrine •Psychodynamic
system Mood factors
•Immune system Disorder
•Sleep
Social
dysfunction
•Support system
(social support)

72. Integrative model of Etiology
Biological
Factors
Psycho-
logical Mood
Factors Vulnerability Disorder
Social
Factors

73. Threshold model
Threshold for mood disorder
Stress
Vulnerability
Low Vulnerability High Vulnerability

74.  Depression has a Multifactorial etiology  Interactions
b/w multiple factors.
 HPA axis disbalance may have a central role in making a
person vulnerable to depression
 Strong genetic predisposition specially in case of
Bipolar disorders
 Neurotransmitters play central role in development of
depression that too the Trimonoaminergic NTs (NE, 5HT,
DA)
 No single NT can be implicated in pathophysiology of
depression it‟s the interaction among various NTs which
causes mood disorders

75.  BDNF:- level is decreased in depression atrophy of
vulnerable neurons in hippocampus depression
 CRH level is increased in depression and is
responsible HPA axis dysfunction. So CRH antagonists
(Antalarmin; Pexacerfont;; Astressin-B) may have
promising results in depression
 Mood disorders show “Kindling phenomenon”. Thus
severity increases with subsequent episodes..so
prophylaxis is important
 Anticonvulsants (Valproic acid & Carbamazepine)
act against this kindling process and prevent
recurrences.

76.  Seligman‟s learned helplessness may explain the
motivational and emotional deficits in depression
 Each and every symptom of Depression & Mania can
hypothetically linked to specific brain area(or
circuit) and to specific NT operating in that circuit.
 So attempts should be made to develop drugs that
modify NT in those specific areas
 So that specific symptoms can be targeted
separately causing a better remission