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, , 2003

DEPRESSION NORMAL MOOD RECOVERY OR REMISSION EPISODE OF DEPRESSION TIME months

acute weeks continuation 4-9 months maintenance 1 or more years REMISSION RECOVERY DEPRESSION NORMAL MOOD 100% TIME

5-4 Stahl S M, Essential Psychopharmacology (2000) acute weeks continuation 4-9 months maintenance 1 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% RESPONDERSMEDICATION medication started 33% NON- RESPONDERS

5-10 Stahl S M, Essential Psychopharmacology (2000) 8 weeks DEPRESSION NORMAL MOOD 33% RESPONDERSPLACEBO placebo started 67% NON- RESPONDERS

5-11 Stahl S M, Essential Psychopharmacology (2000) DEPRESSION NORMAL MOOD 50% continue response PLACEBO SUBSTITUTION antidepressant treatment placebo 50% relapse

5-12 Stahl S M, Essential Psychopharmacology (2000) DEPRESSION NORMAL MOOD 90% continue response DRUG CONTINUATION 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

NE (norepinephrine) tyrosine transporter TYR TOH DOPA DDCDA DBH NOREPINEPHRINE IS PRODUCED

NOREPINEPHRINE IS DESTROYED COMT destroys NE norepinephrine 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 receptor postsynaptic 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 2Attention

Limbic EmotionsAgitation Energy 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 D2D3 D4 D5 dopamine transporter

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

5HT (Serotonin) SEROTONIN IS PRODUCED tryptophan transporter TRY-OH 5HTP AAADC Tryptophan

serotonin transporter MAO SEROTONIN IS DESTROYED

SEROTONIN RECEPTORS alpha 2 hetero receptor 5HT1D autoreceptor 5HT1A serotonin transporter 5HT2A 5HT2C 5HT35HT4 5HTX 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 neuron presynaptic alpha 2 autoreceptor postsynaptic alpha 2 hetero receptor presynaptic alpha 2 autoreceptor alpha 1 receptor norepinephrine neuron 5HT accelerator 5HT brake

Serotonin Receptors 5HT 1a receptors are presynaptic and control the release of serotonin from the presynaptic terminal, but there are also post-synaptic 5HT 1a receptors. Many studies find increased 5HT 1a receptors in postmortem brains of depressed suicide patients Recent studies show 5HT 1a receptor knock-out mice have increased anxious behavior, and “knocking in” the 5HT 1a receptor with a cortex- specific promoter ameliorates the anxious behavior.

Serotonin Receptors 5HT 2a receptors –Post-synaptic receptor –Binding to 5HT 2a receptors in platelets is increased, particularly related to suicidal tendencies –Increased number of 5HT 2a receptors in post- mortem brain tissue in only some studies

5HT2A

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 CortexMood

Basal Ganglia OCD Akathisia/ Agitation

LimbicAnxiety

HypothalamusAppetite/bulimia

Sleep CentersInsomnia

Spinal CordSexual Dysfunction

Monoamine Receptor Hypothesis of Depression Normal functioning Decrease in NT Receptors up- regulate due to lack of NT