Etiology of mood disorder by swapnil agrawal

1. Neurobiology of mood disorders Presenter- Dr. Swapnil Agrawal Guide- Dr. D.K.Sharma Professor & Head, Dept of Psychiatry, Govt Medical College, Kota

2. Contents Introduction Classification Etiology

3. introduction 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. Classification (Icd-10) 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. etiology No single etiological factor Multifactorial etiology Much more data available for etiology of Depression than of Mania.

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

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

8. Genetic factors

9. Genetic factors 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 UNIPOLAR DISORDER 20-30% 20-30% AVERAGE AGE OF ONSET 21 yrs 27 yrs

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

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)

13. neurotransmitters

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

15. Tri- monoaminergic nt system 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. NE 5HT 5HT 5HT DA 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

21. 1. norepinephrine 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 .

22. 2. Serotonin 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 .

23. 3. dopamine 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 .

24. Other nt disturbances 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.

25. 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 .

26. 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.

27. 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.

28. Recent view… 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.

29. Brain derived neurotrophic growth factor ( Bdnf ) 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.

30. KINDLING HYPOTHESIS 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 .

31. Symptoms & circuits in depression

32. DSM-IV symptoms of depression.

33. 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. WOW!!

34. 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 .

35. 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  Reduction of positive affect  mainly due to diffuse DA reduction Increase in negative affect  mainly due to diffuse 5HT reduction 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..!!

36. Symptoms & circuits in mania

37. DSM-IV symptoms of mania.

38. 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 Matching mania symptoms to circuits.

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

40. (Cognitive symptoms)

41. Some interesting neuroimaging in mood disorders

42. (Cognitive Symp ) (Emotional Symp )

43. Neuroendocrine abnormalities 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 Dysregulation of the release of Growth hormones

44. 1. 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 (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.

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

46. 2. Thyroid axis Disturbed in about 5 to 10% of persons with depression About 1/3 rd 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).

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

48. Immunological changes 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.

49. Sleep dysfunctions Initial and terminal insomnia Multiple awakenings & 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 In depression

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

51. Psychological factors

52. STRESSFULL LIFE EVENTS 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 1 st 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)

53. b. Personality & behavioral factors 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.

54. c. Psychodynamic factors 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

55. 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.

56. d. Cognitive factors 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’)

57. 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

58. Psychological Stressful life events Personality factors Psychodynamic factors Cognitive factors

59. Social factors

60. Social factors: Social support 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

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

62. Social Factors Psycho- logical Factors Biological Factors Integrative model of Etiology Protective factors Stressor Mood Disorder Vulnerability

63. Threshold for mood disorder Threshold model

64. Take home message…. 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

65. 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.

66. 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

67. By- Dr.swapnil agrawal 2 nd yr resident, dept. of psychiatry, govt. medical college, kota ( rajasthan ) india