Neurobiology of mood

disorders

Presenter- Dr. Swapnil Agrawal

Guide-Dr. D.K.SharmaProfessor & Head,

Dept of Psychiatry,Govt Medical College,

Kota

CONTENTS1) Introduction2) Classification 3) Etiology

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.

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

ETIOLOGY No single etiological factor Multifactorial etiology

Much more data available for etiology of Depression than of Mania.

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

MoodDisorder

SocialFactors

Psycho-logicalFactors

BiologicalFactors

Integrative model of Etiology

Mood

DisorderVulnerability

GENETIC FACTORS

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

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%)

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)

NEUROTRANSMITTERS

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)

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.

NE5HT

5HT5HT

DA

NE

Norepinephrine regulation of serotonin. Norepinephrine regulates serotonin release. It does thisby acting as a brake on serotonin release at alpha 2 receptors on axon terminals 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 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 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 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

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.

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.

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.

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.

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 nodepression present.

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.

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.

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.

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.

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.

SYMPTOMS & CIRCUITS IN

DEPRESSION

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.

WOW!!

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 neurotransmitter centers; 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 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..!!

SYMPTOMS & CIRCUITS IN MANIA

DSM-IV symptoms of mania.

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.

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 hyperactivitiyIn OFC,DLPFC,VMPFC

Regulated by 5HT, DA & NE

(Cognitive symptoms)

SOME INTERESTING NEUROIMAGING IN MOOD DISORDERS

(Cognitive Symp)

(Emotional Symp)

NEUROENDOCRINE ABNORMALITIES

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 gland3. Dysregulation of the release of Growth

hormones

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.

Adverse childhood experiences

HPA axis function

CORTISOL

DecreasedNA function

Decreased5HT function

Prefrontal cortexHippocampus

Depressive syndrome

Current Stress

Genetlic factors

Past Depressiveepisode

2. THYROID AXIS 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).

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.

IMMUNOLOGICAL CHANGES1. 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.

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

Biological

Family and genetics

Neurotransmitters

Neuro-endocrine system

Immune system

Sleep dysfunction

PSYCHOLOGICAL FACTORS

A. 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 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)

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.

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

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.

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’)

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

Psychodynamic factors

Cognitive factors

SOCIAL FACTORS

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

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

MoodDisorder

SocialFactors

Psycho-logicalFactors

BiologicalFactors

Integrative model of Etiology

Mood

DisorderVulnerability

Low Vulnerability High Vulnerability

Stress

Vulnerability

Threshold for mood disorder

Threshold model

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

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

BY-DR.SWAPNIL AGRAWAL

2ND YR RESIDENT,DEPT. OF PSYCHIATRY,

GOVT. MEDICAL COLLEGE,KOTA(RAJASTHAN)

INDIA