Unipolar Depression

Unipolar Depression

• Sad & helpless every day for weeks

• Loss of interests, energy, appetite

• Feel worthless

• Contemplate suicide

• Difficulty in concentrating

• Restless agitation

• Little or no pleasure from eating or sex

Unipolar Depression• 2 X as often in women as in men

• ~ 5% of adults in US have “clinically significant” depression

• The lifetime risk for Major depressive disorder in community samples has varied from 10% to 25% for women and from 5% to 12% for men.

• Approximately 50%-60% of individuals with major

depressive disorder, single episode, can be expected to

have a second episode. Individuals who have had two

episodes have a 70% chance of having a third, and

individuals who have had three episodes have a 90%

chance of having a fourth.

Unipolar Depression• Relative Risk of MDD is 2-5x greater in relatives of

depressed patients than controls

• A genetic component

– 60% concordance for monozygotic twins

– 20% for dizygotic twins

– Especially for early-onset & among female relatives

– Not a single-gene defect

Serotonin and Transporter Genes

Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene Caspi et al. Science Vol 301, Issue 5631, 386-389, 2003

DEPRESSION

NORMAL MOOD

RECOVERY OR REMISSION

EPISODE OF DEPRESSIONEPISODE OF DEPRESSION

TIME6 - 24 months

acute 6 - 12 weeks

continuation4-9 months

maintenance1 or more years

REMISSION

RECOVERY

DEPRESSION

NORMAL MOOD

100%

TIME

5-4 Stahl S M, Essential Psychopharmacology (2000)

acute 6 - 12 weeks

continuation4-9 months

maintenance1 or more years

TIME

DEPRESSION

NORMAL MOOD RELAPSE RECURRENCE

5-5 Stahl S M, Essential Psychopharmacology (2000)

DEPRESSION

NORMAL MOOD

MANIA

HYPOMANIA

MIXED EPISODE

5-9 Stahl S M, Essential Psychopharmacology (2000)

8 weeks

DEPRESSION

NORMAL MOOD

67% RESPONDERS

MEDICATIONMEDICATION

medication started

33% NON-RESPONDERS

5-10 Stahl S M, Essential Psychopharmacology (2000)

8 weeks

DEPRESSION

NORMAL MOOD

33% RESPONDERS

PLACEBOPLACEBO

placebo started

67% NON-RESPONDERS

5-11 Stahl S M, Essential Psychopharmacology (2000)

DEPRESSION

NORMAL MOOD

50% continue response

PLACEBO PLACEBO SUBSTITUTIONSUBSTITUTION

antidepressant treatment

placebo

50% relapse

5-12 Stahl S M, Essential Psychopharmacology (2000)

DEPRESSION

NORMAL MOOD

90% continue response

DRUG DRUG CONTINUATIONCONTINUATION

antidepressant treatment

10% relapse

Monoaminergic Theory of Depression

• Reserpine-(antihypertensive drug) caused depression, depleted monoamine stores in rodent studies

• Iproniazid- (antituburcular drug) elevated mood, blocked degradation of monoamines

• Imipramine-antidepressant effects, blocked reuptake of norepinephrine (and serotonin)

These findings supported the hypothesis that norepinephrine is decreased in depression and elevated with mania and in effective treatments of depression.

Indoleamine Hypothesis of Depression

• Serotonin is functionally deficient in depression– Decreased brain 5-HT and CSF 5-HIAA in

many depressed patients– Antidepressants tend to increase central

serotonin transmission– Depressed patients show reduction in 5-HT

reuptake sites– Blunted neuroendocrine challenges

Neurotransmitter Hypothesis of Mood Disorders

• Led to catecholamine hypothesis– NE ↓ in depression and in mania– 5-HT ↓ production or reuptake in depression

• Flaws: depression or mania not reliably produced and clinical response exceeds mechanism of action of drug

Neurobiology of Mood Disorders

• Neuroendocrine abnormalities: reflect central neurotransmitter dysfunction– hyperactivity of HPA: increased cortisol,

nonsuppression of cortisol in DST– blunting of TSH release following TRH infusion– blunting of GH release with alpha-2 adrenergic

agonism and serotonin-mediated increases in prolactin

Kindling-Sensitization Hypothesis of Mood Disorders

• Suggests that 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

MAO enzyme destroying neurotransmitter

monoamine neurotransmitter

NORMAL STATE -- no depression

MONOAMINE HYPOTHESIS

DEPRESSION -- caused by neurotransmitter deficiency

Increase in neurotransmitters causes return to normal state

MAO inhibitor blocks the enzyme from destroying monoamine neurotransmitter

reuptake pump blocked by antidepressant

Norepinephrine Synthesis and Metabolism

Tyrosine L-Dopa Dopamine Norepinephrine

Tyrosine Hydroxylase

Metabolites (MHPG)

Epinephrine

COMT Monoamine oxidase

NE (norepinephrine)

tyrosine transporter

TYR

TOH

DOPA

DDC DA

DBH

NOREPINEPHRINE IS PRODUCED

NOREPINEPHRINE IS DESTROYED

COMT destroys NEnorepinephrine

transporter

MAO

Noradrenergic Receptors

• receptors are both presynaptic and postsynaptic; often elevated in depressed patients in platelets and brains of suicide patients

• ß receptors are postsynaptic; often decreased in brains of suicide patients

There can be noradrengeric changes with depressive and anxious disorders

We don’t know if these are the cause of depression or a result of

depression.

NOREPINEPHRINE RECEPTORS

presynaptic alpha 2 autoreceptor

postsynaptic alpha 2

receptorpostsynaptic beta 1 receptor

alpha 1 receptor

terminal alpha 2 autoreceptor

somatodendritic alpha 2

autoreceptor

NE occupying somatodendritic autoreceptor causes a decrease in firing and a decrease of NE release

NE

NE occupying terminal alpha 2 receptor halts release of NE

NE

Norepinephrine Pathways

Locus Coeruleus

beta 1 receptor

DepressionFrontal 1

alpha 2 receptor

Frontal 2 Attention

Limbic

EmotionsAgitationEnergy Level

Dopamine

• Some studies show lower levels of DOPAC and HVA in urinary and CSF samples in depressed patients.

• In contrast, elevated levels of mesolimbic dopamine found in some patients with delusional depression.

• Changes in the HPA axis may lead to changes in dopaminergic system

tyrosine transporter

TOH

TYR

DOPA

DDC

DA (Dopamine)

DOPAMINE IS PRODUCED

COMT destroys NE

dopamine transporter

MAO

DOPAMINE IS DESTROYED

DOPAMINE RECEPTORS

presynaptic autorecptor

D1 D2 D3 D4 D5

dopamine transporter

Serotonin

Tryptophan

Tryptophan hydroxylase

5-Hydroxytryptophan Serotonin

5-HIAA

Monoamine oxidase

A number of studies find low CSF 5-HIAA levels in depression.

5HT (Serotonin)

SEROTONIN IS PRODUCEDtryptophan transporter

TRY-OH

5HTP

AAADC

Tryptophan

serotonin transporter

MAO

SEROTONIN IS DESTROYED

SEROTONIN RECEPTORS

alpha 2 hetero receptor

5HT1D autoreceptor

5HT1A

serotonin transporter

5HT2A5HT2C

5HT3 5HT45HTX

5HTY

5HTZ

5HT1D

norepinephrine

serotonin

alpha 2 hetero receptor

serotonin neuron

alpha 2 hetero receptor

serotonin neuron

norepinephrine

serotonin

alpha 1 receptor

norepinephrine

serotonin

alpha 1 receptor

brake

accelerator

Locus Coeruleus

NE-5HT Interactions

Serotonin Receptors

• 5HT1a receptors are presynaptic and control the release of serotonin from the presynaptic terminal, but there are also post-synaptic 5HT1a receptors.

• Many studies find increased 5HT1a receptors in postmortem brains of depressed suicide patients

• Recent studies show 5HT1a receptor knock-out mice have increased anxious behavior, and “knocking in” the 5HT1a receptor with a cortex-specific promoter ameliorates the anxious behavior.

Serotonin Receptors

• 5HT2a receptors

– Post-synaptic receptor

– Binding to 5HT2a receptors in platelets is increased, particularly related to suicidal tendencies

– Increased number of 5HT2a receptors in post-mortem brain tissue in only some studies

Serotonin Transporter

• Pumps serotonin back into the presynaptic cell

• Decreased SERT activity in platelets of depressed patients, although brain studies less conclusive

• Higher incidence of depression in individuals with short forms of SERT

SSRIs are the most effective antidepressant medications currently

available.

However, screening for effectiveness of SSRIs often does not accurately

predict clinical response.

Serotonin Pathways

Raphe Nucleus

Frontal Cortex Mood

Basal Ganglia OCDAkathisia/Agitation

Limbic Anxiety

Hypothalamus Appetite/bulimia

Sleep Centers Insomnia

Spinal Cord Sexual Dysfunction