Etiopathogenesis of bipolar disorder

A comprehensive presentation on BPAD.

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

2. outline 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?

5. 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.

6. E tiology of Bipolar disorder

7. OVERVIEW OF ETIOLOGICAL FACTORS GENETIC FACTORS PSYCHOSOCIAL FACTORS BIOLOGICAL FACTORS A s supported by family and twin studies. T emperament and behaviour Psychodynamic factors Cognitive faults (distortions) Social and family relationship gender Neurotransmitters Neuro -endocrine system Immune system Sleep dysfunction

8. Genetic E tiology

9. Adoption studies The study of adoptees who are separated from their biological parents has consistently favoured the gene–environment hypothesis in the e tiology 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 .

10. 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.

11. 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 R esponse Element Binding protein) on Chr.2 – carry strong linkage to unipolar disorder.

12. 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. A n association between cysteine–adenine–guanine (CAG) tri-nucleotide repeats and bipolar affective disorder is seen in some studies.

13. NEUROTRANSMITTERS

14. MONOAMINERGIC NT I NTERACTION 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.

15. Norepinephrine as an accelerator of serotonin release

16. Norepinephrine as a brake on serotonin release

17. 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.

18. Monoamine hypothesis of depression

19. 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.

20. 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

21. 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 .

22. 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.

23. Stress, BDNF, and brain atrophy in depression

24. 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

25. 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.

26. 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.

27. 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.

28. 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.

29. 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. Neuroendocrine abnormalities

30. HPA axis ( H ypothalamo -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.

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

32. 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

33. 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.

34. 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. Immunological changes

35. 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. Sleep dysfunctions

36. R eduction 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.

37. 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.

38. PSYCHOSOCIAL FACTORS

39. 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 . E xample - 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 .

40. 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. E xtroverts 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'.

41. 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 .

42. 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

43. PSYCHODYNAMIC FACTORS IN MANIA Most theories view manic episodes as a defence against underlying depression. L ike inability to tolerate a tragedy such as loss of a parent. Manic state may also result from a tyrannical superego W hich produces intolerable self criticism T hat is then replaced by euphoric self-satisfaction

44. 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’)

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

46. SOCIAL AND 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 D escriptive studies have suggested that marital conflict correlates highly with concomitant depression.

47. GENDER F or men, marriage confers a protection against illness, while it appears to be associated with higher rates of depression for women. W ithin the marriage the traditional female role is limiting, restricting, and even boring, which may lead to depression . T he 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. R esponse 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.

48. 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 .

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