Etiology of mood disorder by swapnil agrawal
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  • NOTE:-Serotonin (5HT2A) at some places in brain can also facilitate DA release..eg. Stimulation of 5HT2A receptors also causes increase glutamate release which in turn causes increased DA release in MESPLIMBIC pathway.!!
  • Cell bodies of all ne neurons lies in locus ceruleus.Cell bodies of 5ht neurons lie in raphe nucleus.
  • This may explain the MoA if atypical antipsychotics in depression..5HT2A inhibit DA release in the PFC.So atypical antipsychotics having full antagonistic activity of 5HT2A receptor will disinhibit DA release so ultimately DA is increased in PFC leading to improvement of negative affect symptoms of depression..!!!
  • 5HT2C receptors regulate dopamine in nucleus accumbens. Serotonin (5HT) also regulates release of dopamine (DA) in the nucleus accumbens via 5HT2C receptors on two types of gamma-aminobutyricacid (GABA) neurons. First, stimulation of 5HT2C receptors on GABA interneurons within the brainstem (on theright) causes release of GABA there, which in turn inhibits activity of ascending mesolimbic dopamineprojections. This results in reduced DA release in the nucleus accumbens. Second, stimulation of 5HT2Creceptors on GABA neurons that project out of the brainstem and into the prefrontal cortex (on the left) leads toinhibition of descending glutamate projections to brainstem dopamine neurons. This, in turn, also leads toreduced DA in the nucleus accumbens.
  • AMPT(alfa methyl para tyrosine) is drug which inhibits enzyme Tyrosine Hydroxylase which catalyzes the conversion of the amino acid tyrosine to L-Dopa, a precursor of both NE & DA.
  • This may explain the MoA if atypical antipsychotics in depression..5HT2A inhibit DA release in the PFC.So atypical antipsychotics having full antagonistic activity of 5HT2A receptor will disinhibit DA release so ultimately DA is increased in PFC leading to improvement of negative affect symptoms of depression..!!!
  • Fatigue MENTALfatigue—due to deficient NT functioning in PFC  PHYSICAL fatigue—due to deficient NT in rest areas(spinal cord, striatum.nucleusaccumbens)
  • Neuroimaging of brain activation in depression. Neuroimaging studies of brain activation suggest that resting activity in the dorsolateral prefrontal cortex (DLPFC) of depressed patients is low compared tothat in nondepressed individuals (left, top and bottom), whereas resting activity in the amygdala andventromedial prefrontal cortex (VMPFC) of depressed patients is high compared to that in nondepressedindividuals (right, top and bottom).
  • Depressed patient's neuronal response to induced sadness versus happiness. Emotionalsymptoms such as sadness or happiness are regulated by the ventromedial prefrontal cortex (VMPFC) and theamygdala, two regions in which activity is high in the resting state of depressed patients (left). Interestingly,provocative tests in which these emotions are induced show that neuronal activity in the amygdala is overreactiveto induced sadness (bottom right) but underreactive to induced happiness (top right).
  • Manic patient's neuronal response to no-go task. Impulsive symptoms of mania, such as risktaking and pressured speech, are related to activity in the orbital frontal cortex (OFC). Neuroimaging data showthat this brain region is hypoactive in manic (bottom right) versus normal (bottom left) individuals during theno-go task, which is designed to test response inhibition.
  • A Corticotropin releasing hormone antagonist is a specific type of receptor antagonist which blocks the receptor sites for Corticotropin releasing hormone (also known as Corticotropin releasing factor (CRF)), blocking therefore the consequent secretions of ACTH and cortisol.There are four subtypes of this receptor known at present, defined as CRF-1, CRF-2a, CRF-2b and CRF-2g. Three of these receptors are expressed only in the brain, CRF-1 in the cortex and cerebrum, CRF-2a in the lateral septum and hypothalamus and CRF-2g in the amygdala. CRF-2b is expressed in the choroid plexus and cerebral arterioles in the brain, but is mainly expressed peripherally, on the heart and skeletal muscle tissue.[1]The main research into CRF antagonists to date has focused on antagonists selective for the CRF-1 subtype. Several antagonists for this receptor have been developed and are widely used in research, with the best-known agents being the selective CRF-1 antagonist antalarmin and a newer drug pexacerfont, although several other ligands for this receptor are used in research, such as LWH-234, CP-154,526, NBI-27914 and R-121,919. Antagonists acting at CRF-2 have also been developed, such as the peptide Astressin-B,[2] but so far no highly selective agents for the different CRF-2 subtypes are available.
  • REMs are under the direct control of cholinergic neurons in the pons, which are tonically inhibited by histaminergic and noradrenergic neurotransmission during wakefulness.During sleep, inhibitory 5HT projection from the dorsal raphe nuclei phasically suppress REM. Pharmacological manipulations that increase central cholinergic activity lighten sleep and increase phasic REM activity. Dietary depletion of 5HT and exogenous administration of glucocorticoidssimilarily can increase phasic REM indices.
  • Learned helplessness--- dogs in lab---electrical shocks from which they could not escape—showed behaciors that differentiaed them dogs that had not been exposed to such uncontrollable evengts.The dogs exposed to the shocks ould not cross a barrier to stop the flow of electric shck when put in a new learning sitration,,they remained passive and did not move.So they had both cognitive motivational deficit(they would not attempt to escape the shock) As well as emotional deficit (i.e. decreased reactivity to shock)..
  • Cognitive distortions include- Arbitrary interference, selective abstraction, overgeneralisation, personalisatiion.
  • The main research into CRF antagonists to date has focused on antagonists selective for the CRF-1 subtype. Several antagonists for this receptor have been developed and are widely used in research, with the best-known agents being the selective CRF-1 antagonist antalarmin and a newer drug pexacerfont, although several other ligands for this receptor are used in research, such as LWH-234, CP-154,526, NBI-27914 and R-121,919. Antagonists acting at CRF-2 have also been developed, such as the peptide Astressin-B,[2] but so far no highly selective agents for the different CRF-2 subtypes are available.

Etiology of mood disorder by swapnil agrawal Etiology of mood disorder by swapnil agrawal Presentation Transcript

  • 1) Introduction2) Classification3) Etiology
  •  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.
  •  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
  •  No single etiological factor Multifactorial etiology Muchmore data available for etiology of Depression than of Mania.
  • Biological Psychological•Family and •Stressful life eventsgenetics •Personality factors•Neurotransmitters •Cognitive factors•Neuro-endocrine •Psychodynamicsystem Mood factors•Immune system Disorder•Sleep Social dysfunction •Support system (social support)
  • Integrative model of EtiologyBiological Factors Psycho- logical Mood Factors Vulnerability Disorder Social 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 DISORDERLIFE TIME RISK About 1% 10-20%SEX RATIO 1:1 1:2IN FIRST DEGREERELATIVES:-LIFETIME RISK FOR BAD About 10% About 20%LIFETIME RISK FOR 20-30% 20-30%UNIPOLAR DISORDERAVERAGE AGE OF 21 yrs 27 yrsONSET
  • 2) TWIN STUDIES- Concordance rates- monozygotics>dizygotics bipolar>unipolar proband BIPOLAR 1 DISORDER MAJOR DEPRESSIVE DISORDERMZ 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.
  • 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!
  • 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)
  •  NT Deficient in Depression-1. Serotonin2. Norepinephrine3. Dopamine4. Gamma-aminobutyric acid (GABA)5. Brain-derived neurotrophic factor (BDNF)6. Somatostatin NT excess en Depression-1. Acetylcholine2. Corticotrophin Releasing Hormone (CRH)
  •  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
  • Norepinephrine regulation of serotonin. Norepinephrine regulates serotonin release. It does thisby acting as a brake on serotonin release at alpha 2 receptors on axonterminals and as an accelerator ofserotonin release at alpha 1 receptors at the somatodendritic area.
  • Norepinephrine as a brake on serotonin release
  • Norepinephrine as an accelerator of serotonin release
  • 5HT2A receptors regulate norepinephrine and dopamine. Serotonin (5HT) regulates release of (NE) and (DA) in the prefrontal cortex via 5HT2A receptors located at thesomatodendritic 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 ofthese neurotransmitters into the prefrontal cortex.In addition, binding of 5HT at 5HT2A receptors on some GABA interneurons in thebrainstem increases GABA release, which then inhibits NE and DA release.
  • 5HT2C receptors regulate norepinephrine and dopamine.(5HT) also regulates release of (NE) and (DA) in the prefrontal cortex via 5HT2C receptorslocated on (GABA) interneurons in the brainstem. Binding of 5HT at 5HT2C receptors on these GABA interneurons increases GABA release, whichthen inhibits NE and DA release from their respective neurons
  •  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.
  •  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.
  •  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.
  •  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.
  • Classic monoamine hypothesis of depression, part 1.According to the classic monoamine hypothesis of depression, when there is a "normal" amountof monoamine neurotransmitter activity, there is nodepression present.
  • Classic monoamine hypothesis of depression, part 2. The monoamine hypothesis of depression posits that if the "normal" amount ofmonoamine neurotransmitter activity becomes reduced,depleted, or dysfunctional for some reason, depression may ensue.
  • Monoamine receptor hypothesis of depression.The monoamine receptor hypothesis of depression extends the classic monoamine hypothesis ofdepression, positing that deficient activity of monoamine neurotransmitters causesupregulation of postsynaptic monoamine neurotransmitter receptors, and that this leadstodepression.
  •  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.
  •  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.
  •  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.
  • DSM-IV symptoms of depression.
  •  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.
  • Matching depression symptoms to circuitsFunctionality in each brain region is hypotheticaily associated with a different constellation ofsymptoms. PFC, prefrontal cortex; BF, basal forebrain; S, striatum; NA, nucleus accumbens; T,thalamus; HY, hypothalamus; A, amygdala; H, hippocampus; NT, brainstem neurotransmittercenters; SC, spinal cord; C,cerebellum.
  •  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 reduction2. Increase in negative affect mainly due to diffuse 5HT reduction3. 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..!!
  • DSM-IV symptoms of mania.
  • 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
  • Note:- Risk taking,Grandiosity, Pressured speechFlight of Ideas, (poor impulse control)Racing thoughts Due to hyperactivitiyAre due to hyperactivity In OFC,DLPFC,VMPFCIn the nucleusaccumbens Regulated by 5HT, DA & NERegulated by 5HT & DA
  • (Cognitive symptoms)
  • (Emotional Symp)(Cognitive Symp)
  •  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
  •  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.
  • Adverse childhood experiences HPA axis functionCurrent Stress CORTISOL Decreased DecreasedGenetlic factors NA function 5HT function Prefrontal cortex HippocampusPast Depressive episode Depressive syndrome
  •  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).
  •  GH secretion stimulated by NE & DA inhibited by somatostatin & CRH(from hypothalamus) CSF somatostatin levels- decreased in depression, and increased in mania.
  • 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.
  •  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
  • BiologicalFamily and geneticsNeurotransmittersNeuro-endocrinesystemImmune systemSleep dysfunction
  •  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)
  •  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.
  •  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
  •  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.
  •  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‟)
  • 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
  • PsychologicalStressful life eventsPersonality factorsPsychodynamicfactorsCognitive factors
  •  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
  • Biological Psychological•Family and •Stressful life eventsgenetics •Personality factors•Neurotransmitters •Cognitive factors•Neuro-endocrine •Psychodynamicsystem Mood factors•Immune system Disorder•Sleep Social dysfunction •Support system (social support)
  • Integrative model of EtiologyBiological Factors Psycho- logical Mood Factors Vulnerability Disorder Social Factors
  • Threshold modelThreshold for mood disorderStressVulnerability Low Vulnerability High Vulnerability
  •  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
  •  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.
  •  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