A comprehensive presentation on BPAD.

1. Presenter: Dr. Udayan Majumder
Resident in Psychiatry, RIMS
Date : 14th December 2015

2. • In this presentation, we will be able to know about :
 Brief outline about bipolar disorder
 Etio-pathogenesis of Bipolar Disorders

3. INTRODUCTION
ON THE NATURE OF EMOTIONS
• Traditionally, feeling has been used to describe a
positive or negative reaction to an experience.
• Affect (broad term) is used to cover mood,
feeling, attitude, preferences and evaluations at
the present time.
• Mood is more prolonged prevailing stage of
disposition.
• Emotion is used for spontaneous and transitory
experience similar to but not identical to feeling,
as it is not incorporate the physical component of
the experience.

4. • Mood describes the state of the self in relation to Its
environment.
• Mood can be normal or pathological.
• Pathological mood- mood from which the patient
suffers or mood that causes suffering to others.
• Two questions concerning the mood of the patients
1 - is the person suffering?
2 - is the expression of mood inappropriate in this
social setting?

7. Definition of Bipolar Disorder
Bipolar I Disorder
 For a diagnosis of bipolar I disorder, it is necessary to
meet the criteria for a manic episode. The manic episode
may have been preceded by and may be followed by
hypomanic or major depressive episodes.
Bipolar II Disorder
 For a diagnosis of bipolar II disorder, criteria have
been met for at least one hypomanic episode and at
least one major depressive episode.

9. OVERVIEW OF ETIOLOGICAL FACTORS
GENETIC FACTORS
PSYCHOSOCIAL FACTORSBIOLOGICAL FACTORS
• As supported by family and twin studies.
• Temperament and behaviour
• Psychodynamic factors
• Cognitive faults (distortions)
• Social and family relationship
• gender
• Neurotransmitters
• Neuro-endocrine system
• Immune system
• Sleep dysfunction

11. Adoption studies
• The study of adoptees who are separated from their
biological parents has consistently favoured the
gene–environment hypothesis in the etiology of
mood disorders.
• These studies have shown that the biological
children of affected parent remain at increased risk
of mood disorder even if they are adopted by non
affected family.
Examples :-
• An excess of biological mothers with substance
abuse was found among adoptees with depression.
• More alcoholism was observed in the biological
relatives of depressed adoptees than in the biological
relatives of non-depressed adoptees.

12. Twin studies
• Concordance rates- monozygotics > dizygotics
bipolar > unipolar proband
• The members of twin pairs concordant for bipolar
disorder and depression had the same syndrome more
often than expected by chance and this resemblance
was greater in monozygotic than in dizygotic pairs.
.
MZ TWIN
DZ TWIN
Bipolar 1
disorder
60-70%
20%
MDD
50%
20%

13. LINKAGE DISEQUILIBRIUM
• Chromosomes Involved :-
18p11 - Runs over family, transmitted through
mother
21q - Linkage of both bipolar disorder and
schizophrenia
22q11 – BCR gene, neuronal growth and axonal
guidence
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.

14. Anticipation and expanded tri-nucleotide
repeat sequences
• Severity of disease worsens in succeeding
generations or age of onset of disease is earlier in
succeeding generations.
• An association between cysteine–adenine–
guanine (CAG) tri-nucleotide repeats and bipolar
affective disorder is seen in some studies.

16. MONOAMINERGIC NT INTERACTION
• The 3 principle NTs involved in mood disorders are:-
 Norepinephrine (NE)
 Serotonin (5HT)
 Dopamine (DA)
• These monoamines work in a way that action of
one is influenced by other.
• 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.

20. Norepinephrine as an accelerator of serotonin release

21. Norepinephrine as a brake on serotonin release

22. 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.

23. Monoamine hypothesis of
depression

24. 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.

25. • 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

26. 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 up-regulation of postsynaptic monoamine neurotransmitter
receptors, and this leads to depression.

27. NEWER STUDIES
• Research is now turning to the possibility that in
depression there may be a deficiency in
downstream signal transduction of the
monoamine neurotransmitter and its
postsynaptic neuron that is occurring in the
presence of normal amounts of neurotransmitter
and receptor.
• Thus, the hypothesized molecular problem in
depression could lie within the molecular events
distal to the receptor, in the signal transduction
cascade system, and in the appropriate gene
expression.

29. BDNF (Brain-derived neurotropic factor)
• BDNF plays a role in the proper growth
and the maintenance of neurons and
neuronal connection.
Under chronic stress the gene for BDNF is repressed
Atrophy of vulnerable neurons in hippocampus
Depression

30. Stress and the environment: how much stress
is too much stress?
• In a healthy individual, stress can cause a temporary
activation of circuits which is resolved when stressor
is removed.
• When circuit is unprovoked, no symptoms are
produced.
• In the presence of a stressor, circuit is provoked yet
able to compensate for the effects of the stressor.
• Individuals exposed to this type of short- term stress
may even develop resilience to stress, whereby
exposure to future stressors provokes the circuits but
does not result in symptoms.

32. DEVELOPMENT OF STRESS SENSITIZATION
• Prolong activation of circuit due to repeated exposure to
stressors can lead “stress sensitization”.
• Circuits not only become overly activated but remain
overly activated even the stressor is withdrawn.
• But the individual exhibits no symptoms because the
circuits can somehow still compensate for the additional
load.
• However, the individual with stress sensitized circuits is
now vulnerable to the future stressors.
• It may therefore a “pre-symptomatic” state which may be
detectable with brain scans of circuits but not from
psychiatric interviews or patient complaints.

34. PROGRESSION FROM STRESS SENSITIZATION TO
DEPRESSION
• The degree of stress one experiences during early life
affects how the circuits develop and therefore how an
individual responds to stress in later life.
• No stress during infancy may lead to a circuit that
exhibits normal activation during stress in later life.
• Mild stress during infancy may actually cause the
circuits to exhibit reduced activity to stress in later life
and provide some resilience to adult stressors.
• Overwhelming and/or chronic stress from child abuse
may lead to stress sensitized circuits that may be
activated even in the absence of stressor.

36. STRESS AND VULNERABLE GENES:
BORN FEARFUL?
• It has been shown in genetic research that
individuals who are carriers of S variant of
serotonin transporter (SERT) appear to be more
vulnerable to the effect of stress.
• Whereas those who carry the I variant appear to
be more resilient.

38. • Depression has been associated with
dysfunction of the endocrine system,
specifically:
• Elevated levels of the stress hormone Cortisol
(Elevated HPA axis activity).
• Malfunctioning of the Thyroid gland.
• Dys-regulation of the release of Growth
hormones.

39. HPA axis
(Hypothalamo-pituitary-adrenal axis)
• 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.
• Elevated HPA activity in depression has been documented
via Dexamethasone Suppression Test.
• Non-suppresion may implicate a loss of inhibitory
hippocampal glucocorticoid receptors resulting in
increased corticotrophin releasing hormone (CRH) drive
by hypothalamus.
• CRH levels are also elevated in CSF of depressed patients.

40. • Corticosteroids have been found to decrease the
binding of 5HT.
• The dexamethasone suppression test was the first
biological marker of major depressive disorders
(MDD) in humans
• Decreased levels of brain-derived neurotrophic
factor (BDNF) reversed by long-term
administration of antidepressants.

41. • Disturbed in about (5-10)% of persons with
depression
• About 1/3rd of patients have blunted thyroid
stimulating hormone (TSH) response to intra-venous
thyroid releasing hormone(TRH).
• 10% of patients may have circulating anti-thyroid
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 Levo-
thyronine (T3).
Thyroid axis

42. GROWTH HORMONE
• Growth hormone secretion stimulated by
norepinephrine & dopamine and inhibited by
somatostatin and CRH (from hypothalamus)
• CSF somatostatin levels-decreased in
depression and increased in mania.

43. • Lowered proliferative responses of lymphocytes to
mitogens.
• Lowered natural killer cell activity.
• Increase in positive acute phase proteins.
• 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.

44. • Early-morning waking is the most typical in
depression, with the sleep patterns in such
patients being similar to those seen in patients
with mania.
• Trouble getting to sleep, frequent awakenings,
and unsatisfactorily prolonged sleep are also
commonly seen in depression.
• Patients with severe depression or mania may
respond to sleep deprivation with a transient
elevation in mood.

45. • Reduction in the total length of slow-wave sleep
and a shortened latency in the appearance of
rapid eye movement (REM) sleep.
• The cholinergic projections from the hindbrain
may be REM-ON cells, while serotonergic and
noradrenergic cells may be REM-OFF cells. The
disturbed sleep of depression could be due to an
increased cholinergic and/or a decreased
serotonergic/noradrenergic drive.

46. Neuro-Imaging Features
• CAT and MRI scans have consistently shown frequencies of
abnormal hyperintensities in subcortical regions like periventricular
regions, basal ganglia and thalamus in case of depression.
• Ventricular enlargement, cortical atrophy and sulcal widening.
• Depressed patients – decreased caudate nucleus and hippocampal
volumes – More focal defects in neurobehavioral systems.
• PET scans shows decreased anterior brain metabolism, more on the
left side, while decreased metabolism is more prominent in the right
side in case of mania.
• Decreased cerebral blood flow or metabolism in brain, in the
mesocortical and mesolimbic dopamine tracts in depression, as
suggested by some studies.
• Episodes of depression in some studies have strongly revealed
correlation of intrusive ruminations with increased glucose
metabolism in the brain.

49. TEMPERAMENT AND BEHAVIOUR
• The construct of temperament has traditionally
focused upon individual differences in emotionality.
However, affective–motivational processes can be
seen to extend beyond the traditional response-
oriented domain of emotion, influencing a variety of
perceptual and cognitive processes .
• Example- an emotion such as sadness regulates
somatic, autonomic, and endocrine response
systems, while at the same time modulating sensory
channels converging upon these response system.
Thus, the regulatory system of temperament plays a
high-level role in co-ordinating attention and
response to social context and influences nearly
every aspect of experience and behaviour.

50. • Introverts are said to possess relatively reactive
reticular systems, and thus to attain their optimal
level of cortical arousal at relatively low level of
stimulation.
• Extroverts are said to possess relatively unreactive
reticular systems, to have correspondingly high
optimal levels of cortical arousal, and to therefore
approach more intense and novel forms of
stimulation.
• A complementary form of limbic activation
influences the intensity of behaviour. Variability in
the functioning of the limbic activation system
underlies a personality dimension referred to as
‘neuroticism–stability'.

51. • Individuals with reactive limbic systems (i.e.
neurotics) are said to be prone to intense
autonomic discharges, while those with less
reactive limbic systems (i.e. non-neurotics) are
thought to demonstrate autonomic lability.
• On the basis of their reticular and limbic
reactivity, individuals are classified into four
basic types: neurotic extrovert, stable extrovert,
neurotic introvert, and stable introvert.

52. PSYCHODYNAMIC FACTORS IN DEPRESSION
• Depression rooted in an early defect in the attachment
relationship with the caregiver (e.g. 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

53. PSYCHODYNAMIC FACTORS IN MANIA
• Most theories view manic episodes as a defence
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

54. COGNITIVE FACTORS
• According to cognitive theory, depression results from
specific cognitive distortions (illogical ways of
thinking) present in persons prone to depression.
• Depressed patients characteristically have recurrent
negative thoughts ( Automatic thoughts)
• Aaron Beck’s cognitive triad of depression- i.e.
negative views about the self, environment,& future.
• These automatic thoughts persists because of illogical
ways of thinking (Cognitive distortions)
• Depression also predisposed by ‘dysfunctional beliefs’
(eg. ‘if I am not perfectly successful I am nobody’)

55. • Early life experiences
• Formation of dysfunctional beliefs
• Critical events
• Beliefs activated
• Negative Automatic thoughts
• Symptoms of Depression
(Behavioural, motivational, affective, cognitive,
somatic)

56. SOCIALAND FAMILIAL RELATIONSHIPS
• 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
MARITAL DISTURBANCE
• Descriptive studies have suggested that marital conflict
correlates highly with concomitant depression.

57. GENDER
• For men, marriage confers a protection against
illness, while it appears to be associated with higher
rates of depression for women.
• Within the marriage the traditional female role is
limiting, restricting, and even boring, which may
lead to depression.
• The role of child caretaker has consistently been
shown to be associated with both high levels of
stress and a higher incidence of depression for
women.
• Response style theory : According to this theory,
women are more likely than men to have a
ruminative response style, which contributes to the
perpetuation of their depressed mood.

58. • On the other hand, men are more likely to
distract themselves from depressed mood,
thereby dampening their symptoms.
• Finally, there is some evidence to suggest that
the post-partum and the premenstrual periods,
with their associated biological and
psychological changes, represent periods of
increased risk of depression among women.

59. REFERENCES
• Kaplan & Sadock’s Comprehensive Textbook of
Psychiatry 1698-1712
• Stahl’s Essential Psychopharmacology, 4th ed.,
238, 250-76.
• Sims’ Symptoms in the Mind, 4th ed., 319-23.
• Fish’s clinical psychopathology, 3rd ed., 65.
• Oxford Textbook of Psychiatry, 557-62.
• Basic Psychiatry. 61-69