The Neurobiology of Mood Disorders

J. John Mann, MD
Professor of Psychiatry and Radiology

Columbia University

Chief, Department of Neuroscience,

New York State Psychiatric Institute

Mood Disorders are Serious

Start at early age.

Hard to diagnose in youth.

Confused with normal teenage behavior, drug use or other psychiatric illnesses.

Mostly recurrent episodes or chronic illness.

High suicide risk.

Treatment often started late and long-term compliance poor.

Early treatment and episode prevention is better than responding to each new episode.

Why are Mood Disorders Recurrent?

Abnormal brain development.

Why is brain develop not normal? Genetic and developmental effects.

Topics

Neurotransmitter deficiency hypotheses

Hyperactive stress systems

Action of antidepressants

Neurotransmitter Deficiency Hypotheses of Depression

Serotonin

Norepinephrine

Dopamine

Gamma-aminobutyric acid (GABA)

Brain-derived neurotrophic factor (BDNF)

Somatostatin

Neurotransmitter Excess Hypotheses of Depression

Acetylcholine

Substance P

Corticotrophin Releasing Hormone (CRH)

Serotonin in Major Depression

Cerebrospinal Fluid

Neuroendocrine challenges

Platelets

Postmortem brain

Depletion

Imaging

Genes

CSF 5-HIAA in DEPRESSION

An index of serotonin turnover.

Probably lower in depression.

A trait and under genetic control (candidate for genetic cause of depression).

Lowered by maternal deprivation, an effect that persists into adulthood in monkeys.

Serotonin Neuroendocrine Challenges

Serotonin release causes the release of prolactin

Prolactin responses to serotonin are blunted in depression

Blunting present in remitted patients = trait

Effect of Serotonin Depletion in Unipolar Disorders

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 and prevention of future episodes requires ongoing medication.

HPA STRESS AXIS AND SEROTONIN IN MAJOR DEPRESSION

Hypothalamic Pituitary Adrenal Axis (HPA) overactivity (elevated CRH and cortisol, dexamethasone resistance) is present in many patients with severe depression.

Corticosteroids reduce hippocampal 5-HT1A receptor sites in animal studies and may explain reduced hippocampal damage in depression.

Platelets Used as a Serotonin Neuron Model In Studies of Major Depression

Lots of serotonin-related abnormalities.

Serotonin uptake low.

Serotonin transporter sites are fewer.

More 5-HT2A receptors in association with suicidal acts.

5-HT2A signal transduction is blunted in suicidal cases.

Possible link to increased risk of death from myocardial infarction in major depression.

Serotonin 5-HT1A Receptors

Major part of serotonin communication in brain.

Both an autoreceptor and a terminal field post-synaptic receptor.

Role hypothesized in the pathobiology of mood disorders.

Role hypothesized in the action of antidepressants.

Can be studied in postmortem brain and in live patients using PET scanning.

Candidate Serotonin Genes in Depression

Serotonin transporter

Tryptophan hydroxylase

Receptors including 5-HT1A, 5-HT1B and 5-HT2A

Monoamine Oxidase

Results are promising but preliminary

Imply cause and mechanism

Norepinephrine System

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. Depletion of NE with AMPT causes depression in recovered patients but not normals.

Restraint stress in animals causes NE depletion and hopelessness. Hopelessness is part of major depression.

Dopamine Function is Deficient in Major Depression

Parkinson’s Disease associated with depression.

CSF shows low homovanillic acid (HVA).

Neuroendocrine challenges: blunted responses to dopamine agonists

Depletion of dopamine with AMPT causes depression in recovered patients but not normals.

Imaging: nothing found yet.

Postmortem brain: no data

Genes: TH, COMT & MAO

GABA in Major Depression

CSF levels of GABA are lower in depression.

Postmortem brain: fewer GABA neurons.

Imaging: low GABA in cortex.

Genes: N/A

Fewer GABA Neurons in Anterior Cingulate and Entorhinal Cortex in Bipolar Disorders

27% fewer GABA cells in layer II of bipolar group.

No statistically significant difference in pyramidal cells or glia.

No difference in size of pyramidal cells.

Indicates deficit in local circuit neurons or GABA cells in layer II of anterior cingulate in bipolar disorders.

Benes et al., Biological Psychiatry 2001;50:395-406

Similar results reported by others in entorhinal cortex.

Neurotransmitters and Mania: Hypotheses

Deficient serotonergic neurotransmission has been hypothesized as a factor in mania AND depression. Perhaps because it contributes to GABA deficit.

Anticonvulsants as mood stabilizers and anti-manic agents suggest GABA deficiency may contribute to mood instability.

Increased NE and DA activity may underlie mania

ANTIDEPRESSANT ACTION

Enhance serotonin function by SSRI, MAOI, lithium or tricyclic antidepressant medication.

Enhance norepinephrine or dopamine function by NERI or MAOI.

Increased receptor number induced by ECT or enhance signal by second messenger effects.

Enhance GABA function (anticonvulsants).

Infuse BDNFintrathecally (serotonin growth).

WHY IS THERE A DELAYED ONSET OF ACTION of ANTIDEPRESSANTS

SSRIs cause gradual desensitization of 5-HT1A autoreceptors without change in 5-HT1A postsynaptic terminal field receptors, gradually amplifying the serotonin signal.

ECS causes progressive postsynaptic 5-HT1A receptor upregulation, without effect on autoreceptors.

SECOND MESSENGER EFFECTS in ADDITION TO TRANSMITTER EFFECTS

Noradrenergic signal transduction enhancement by tricyclic antidepressants.

Lithium dampens signal transduction (anti-manic effect).

ECT enhances NE and serotonin signal transduction.

All enhance BDNF and possibly brain growth.

ECT or Convulsive Therapy

Upregulate 5-HT2A and 5-HT1A receptors

Enhance signal transduction

BDNF increase and possible benefit via brain growth.

PEPTIDE ANTAGONISTS

Corticotrphin Releasing Hormone

Substance P

Antagonists are being evaluated as antidepressants.

SUCCESSFUL TREATMENT NORMALIZES HPA STRESS SYSTEM OVER-ACTIVITY IN DEPRESSION

HPA overactivity may be reduced by successful antidepressant treatment

Reduced HPA activity may result in more hippocampal 5-HT1A receptors and perhaps hippocampal growth.

Reduction in CRH may reduce the depression symptoms due to CRH itself.

Consequences of Failure to Diagnose and Treat Depression

Social and family relationships damaged.

School failures, job loss and financial dependence.

Suicide.

Brain cell loss or process retraction or atrophy.

Finit and good luck.

Contact me if you are interested in research.


	J. John Mann, MD Professor of Psychiatry and Radiology
	Columbia University
	Chief, Department of Neuroscience,
	New York State Psychiatric Institute


	Start at early age.
	Hard to diagnose in youth.
	Confused with normal teenage behavior, drug use or other psychiatric illnesses.
	Mostly recurrent episodes or chronic illness.
	High suicide risk.
	Treatment often started late and long-term compliance poor.
	Early treatment and episode prevention is better than responding to each new episode.



	Abnormal brain development.


	Why is brain develop not normal? Genetic and developmental effects.


	Neurotransmitter deficiency hypotheses

	Hyperactive stress systems

	Action of antidepressants


	Serotonin
	Norepinephrine
	Dopamine
	Gamma-aminobutyric acid (GABA)
	Brain-derived neurotrophic factor (BDNF)
	Somatostatin


	Acetylcholine

	Substance P

	Corticotrophin Releasing Hormone (CRH)


	Cerebrospinal Fluid
	Neuroendocrine challenges
	Platelets
	Postmortem brain
	Depletion
	Imaging
	Genes


	An index of serotonin turnover.

	Probably lower in depression.

	A trait and under genetic control (candidate for genetic cause of depression).

	Lowered by maternal deprivation, an effect that persists into adulthood in monkeys.


	Serotonin release causes the release of prolactin

	Prolactin responses to serotonin are blunted in depression

	Blunting present in remitted patients = trait


	May explain why 80% of patients have recurrences of major depressive episodes.
	May explain why prevention of relapse back into an episode and prevention of future episodes requires ongoing medication.


	Hypothalamic Pituitary Adrenal Axis (HPA) overactivity (elevated CRH and cortisol, dexamethasone resistance) is present in many patients with severe depression.

	Corticosteroids reduce hippocampal 5-HT1A receptor sites in animal studies and may explain reduced hippocampal damage in depression.


	Lots of serotonin-related abnormalities.
	Serotonin uptake low.
	Serotonin transporter sites are fewer.
	More 5-HT2A receptors in association with suicidal acts.
	5-HT2A signal transduction is blunted in suicidal cases.
	Possible link to increased risk of death from myocardial infarction in major depression.


	Major part of serotonin communication in brain.
	Both an autoreceptor and a terminal field post-synaptic receptor.
	Role hypothesized in the pathobiology of mood disorders.
	Role hypothesized in the action of antidepressants.
	Can be studied in postmortem brain and in live patients using PET scanning.


	Serotonin transporter
	Tryptophan hydroxylase
	Receptors including 5-HT1A, 5-HT1B and 5-HT2A
	Monoamine Oxidase
	Results are promising but preliminary
	Imply cause and mechanism


	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. Depletion of NE with AMPT causes depression in recovered patients but not normals.


	Restraint stress in animals causes NE depletion and hopelessness. Hopelessness is part of major depression.


	Parkinson’s Disease associated with depression.
	CSF shows low homovanillic acid (HVA).
	Neuroendocrine challenges: blunted responses to dopamine agonists
	Depletion of dopamine with AMPT causes depression in recovered patients but not normals.
	Imaging: nothing found yet.
	Postmortem brain: no data
	Genes: TH, COMT & MAO


	CSF levels of GABA are lower in depression.

	Postmortem brain: fewer GABA neurons.

	Imaging: low GABA in cortex.

	Genes: N/A


	27% fewer GABA cells in layer II of bipolar group.
	No statistically significant difference in pyramidal cells or glia.
	No difference in size of pyramidal cells.
	Indicates deficit in local circuit neurons or GABA cells in layer II of anterior cingulate in bipolar disorders.
	Benes et al., Biological Psychiatry 2001;50:395-406
	Similar results reported by others in entorhinal cortex.


	Deficient serotonergic neurotransmission has been hypothesized as a factor in mania AND depression. Perhaps because it contributes to GABA deficit.

	Anticonvulsants as mood stabilizers and anti-manic agents suggest GABA deficiency may contribute to mood instability.

	Increased NE and DA activity may underlie mania


	Enhance serotonin function by SSRI, MAOI, lithium or tricyclic antidepressant medication.
	Enhance norepinephrine or dopamine function by NERI or MAOI.
	Increased receptor number induced by ECT or enhance signal by second messenger effects.
	Enhance GABA function (anticonvulsants).
	Infuse BDNFintrathecally (serotonin growth).


	SSRIs cause gradual desensitization of 5-HT1A autoreceptors without change in 5-HT1A postsynaptic terminal field receptors, gradually amplifying the serotonin signal.
	ECS causes progressive postsynaptic 5-HT1A receptor upregulation, without effect on autoreceptors.


	Noradrenergic signal transduction enhancement by tricyclic antidepressants.

	Lithium dampens signal transduction (anti-manic effect).

	ECT enhances NE and serotonin signal transduction.

	All enhance BDNF and possibly brain growth.


	Upregulate 5-HT2A and 5-HT1A receptors

	Enhance signal transduction

	BDNF increase and possible benefit via brain growth.


	Corticotrphin Releasing Hormone

	Substance P

	Antagonists are being evaluated as antidepressants.


	HPA overactivity may be reduced by successful antidepressant treatment
	Reduced HPA activity may result in more hippocampal 5-HT1A receptors and perhaps hippocampal growth.
	Reduction in CRH may reduce the depression symptoms due to CRH itself.


	Social and family relationships damaged.

	School failures, job loss and financial dependence.

	Suicide.

	Brain cell loss or process retraction or atrophy.