1. mood and emotional disturbances are primary problems

2. may lead to distortions in thought process (thinking organs are shutting down- psychoses)

1. major (unipolar) depression

2. dysthymic disorder (mild but chronic)

3. Depression not otherwise sepcificied (DNOS) 'atypical'

Recovery vs. remission

(getting worse during both)

Recovery- Long term recovery, still better after 1 yr

Recurrence- getting worse during a recovery stage

Remissions- ST improvement

Relapse- getting worse during remission

1. mood symptoms

2. vetetative symptoms-physiologicalsymptoms

-insomnia

-no appetite

-loss of libido

3. cognitive symptoms (difficulty thinking clearly)

1. often improve before mood symptoms w/ tx

2. in atypical depressions vegetative symptoms are opposite (except for low libido)

3. diff drugs are best fo atypical depression (MAOIs)

-67% respond in 8 weeks

-33 % respond w/ placebo (1/2 of above effect is real)

-responders switching to placebo, 50%relapse in 1 yr

-responders not switching to placebo, 15% relapse

Epidemiology

-gender

-age

-genetics

-prevalence

-other rates

-more common in women

-peaks at age 20-40

-family history makes more prone

-5-11% lifetime prevalence

-high rate of recurrence

-high suicide if untreated

3 treatment options for depression

-overall recovery rates

-which tx to pick

1. medication

2. psychotherapy (CBT, interpersonal)

3. ECT- very effective, can't be done constantly so relapse can be a problem. Safer for elderly

20-40% have full recovery no matter what tx is used

No reliable response predictors

-personal/family history may help chose

1. organic disorders (postpartum, grief, dementia)

2. anxiety - SSRIs

3. sleep-drousy w/out addiction

4. eating disorders (bulimia, not anorexia)

5. ADHD

1. Reserpine & hypertension
2. tuberculosis & the MAOIs
3. Imipramine (discovery, mechanism of action)

• comes from plant Rauwolfia serpentina (used in India to treat hypertention and insanity)
• 1952 Ciba isolated active ingrediatent Reserpine)
  • produces sedation & lowered temp (like chlorpromazine)
  • tested as antipsychotic, but had side effect (made ppl depressed)

-depleted brain of 5HT & NE

-depletion lasted a long time (weeks) after only 1 dose, lasteds even after elimination

-slowly transmitter levels restored and sedation dec

-1952, iproniazid used for tx of TB

-saw it improved mood in patients

-studies showed iproniazid inhibited MAO

-1st MAOI

-american psychiatrist, credited w/ founding field of psychopharmacology

-founded reserpine (used for schizophrenia 1st then tranquilizer), lithium and iproniazid (antidepressants)

-discoveries helped lots of ppl leave institutions

Interaction b/ iproniazid and reserpine

-Conclusion

-reserpine put wholes in synaptic vesicles

-Monoamines then exposed to MAO and metabolized

-Iproniazid prevented metabolism, MA levels no de

-increase in mood happens if the reserpine isn't there, no MAO to break them down so more is put in vesicle and more released into cleft

Conclusion: inc MA=inc mood

Ronald Kuhn

-Chlorpromazine's success furthered development of antihistamines

-found imipramine wasn't effective in schizophrenics, but worked in depressed patients

Imipramine: 1st MAO reuptake blocker for antidepressants

-discovered MAOIs blocked reuptake of MA, not inhibited MAO

Exp: injected radioactive NE into ventricles of rat brains, removed brain and washed away extra NE not taking into presynatpic terminal

-measured radioactivity in brain to see how much NE taken up

-repeated exp but gave rats imipramine 1 hr before radioactive tracer

Results: imipramine decreased radioactive NE taken up

-Imipramine increased time NE was available to postsynaptic receptor (more time in synapse)

(more radioactivity=more NE taken up)

-American biochemist & pharmacologist

-received 1970 Nobel prize for physiology of med

-Found mechanism of formation of Noradrenaline and led to catechol-o-methyl transferase (degrades NT when no longer needed)

-led to lots of psychotropic drugs (resets nerve to nerve connections ready to transmit next impulse)

Hypothesis for antidepressant mechanisms

-2 possible mechanisms for drugs

Biogenic Amine Hypothesis of Affective Disorders

-Depression related to a deficit of monoamines at critical synapses where mania is associated with an excess

1. MAOIs let monamines accumulate and more release (back to normal state)

2. reuptake blockers let MA accumulate in synapse (back to normal state)

1. block enzymes that break down NT

2. block reuptake

Problems with Biogenic Amine Hypothesis

(4)

1. No consistent diff in metab olites b/ depressed and ctrl
2. some AD don't block MAO or reuptake
3. no direct relationship b/ clinical effect and monoaminergic effect (unlike D2 w/ APs)
4. Uptake block & MAO inhibition occur immediately, clinical effect takes longer

What happens to MA systems after 1-2 weeks of AD meds?

explains..

-down regulation of certain NE and 5HT receptors occurs about 10 days into tx

-could explain time delay of effect

Monoamine receptor hypothesis

-reuptake blocks inc availability of 5HT in synapse

-5HT actons on presynaptic 5HT1a autorecepture to decrease more release countering med effect initially

-Eventually 5HT1a become down-regulated

-down regulation of autoreceptors increases release

Depressed ppl may have __________ so receptors might ______

Meds make _______ so _________

Depressed ppl may have too little amines so receptors might be upregulated and too sensitive.

Meds make a down regulation so amines are increased

1. depression is caused by increase in receptors that is a result of a transmitter deficiency

2. AD correct defect and improve mood

D1 & D5- stimulate cAMP, D1 prominent in frontal

D2,3,4,

-Inhibit cAMP

-D2 Striatum- Movement

-D3 nucleus accumbens- reward

-D4 frontal cortex- cognition?

NE

-where?

-receptors

-Locus Coeruleus (LC)

-innervates most of CNS except basal ganglia

Alpha (1a,b,c: 2a,b,c,d: 3)

Beta 1-3 (adipocytes- inc metabolism, reduces body fat)

Alpha 1,2 & Beta1 on postsynaptic neuron

Alpha 2 presynaptic on axonal terminal, soma & dendrites

1. agonist- reduces firing (somatodendritic) or release (terminal)

2. antagonist- will enhance activity and release

• Frontal Cortex (mood, attention, cognition)
• Limbic cortex (temporal, emotion, energy)
  • psychomotor agitation- retardation
• Cerebellum- Tremor
• Brainstem- cardiovascular (blood pressure)
• sympathetic NS (leaving spine)
  • heart rate, bladder emptying

5HT

-most important for..

2 main locations (function)

7 other areas (functions

Most important for depression/anxiety

Raphe- somatodendritic auto receptors (inhibit firing)

Limbic system- hippocampus postsynaptic (inhibits)

1. frontal cortex- mood

2. basal gaglia- movement, OCD acting out rituals

3. limbic area- panic/anxiety

4. hypothalmus- appetite

5. brainstem- sleep, emesis (vomitting)

6. spinal - sexsual reflexes

7. peripheral - GI tract

acts on so many places, explains so many side effects

Abnormal MA systems in depression

-No evidence that 5HT or NE are abnormal in depression

1. 5HT precursor NE and metabolite changes inconsistent

2. NE, little correlation b/ metabolites and illness

-alpha/beta downregulated- could be due to LT meds use

-decreased 5HT and NE in brains

-caused relapse of recoverd depressed ppl

-didn't make dep worse if already depressed

-didnt make ctrl group depressed

Supports monoamine hyp of depression (relation b/ depr and level of MA in brain)

1980 & 1990s

All antidepressants increase 5-HT mediated neurotransmission but in different ways

-5HT is inhibitory, if stimulating Raphe, 5HT released in hippocampus and hippocampal neurons are inhibited

-antidepressant tx (ECT, TCA, MAOI, SSRI) suppress hippocampal activity

-1st generation reuptake blockers (TCAs): tricyclics, name given bc of structure, didn't know what they did

-2nd generation reuptake blockers (SSRIs)

-3rd generation- dual uptake blockers, 5HT2 antagonists, adrenergic agents

-Monamine Oxidase Inhibitors (MAOIs)

-Experimental Agents

1st generation

aka

therapeutic action

side effects

1st generation: hetero (tric) cyclic AD

-therapeutic action- block of monoamine reuptake

Side effects (similar to AP):

-alpha 1 antagonism- orthostatic hypotension, dizzy

-histamine antagonism- sedation weight gain

-anticholinergic antagonism

-cardiac arrhythmia, arrest, death - Na channel block in heart & brain

- amitriptyline- Elavil

-Desipramine- norpramin

Imipramine- tofranil

-Notriptyline- aventyl, pamelor

-clomipramine- anafranil

2nd generation effect

-AKA

-therapeutic effect

-diff in side effects

Selective serotonin Reuptake Inhibitors

Therapeutic effect: selective and potent 5HT uptake blocker

-midbrain raphe to frontal cortex (AD effect)

-midbrain raphe to hypothalamic nuclei (antibulimic)

Side effect: no sodium channel block, much safer than TCAs

Least: phenthylamine-venflaxine (effexor)

Most: Aminoketone - Bupropion

1. loss of sexual desire or anorgasmia (prob bc issue w/ depression too)

2. stimulation - increased heart rate, tremor, anxiety, insomnia

3. GI upset- nausea diarrhea

Other side effects:

-cognitive problems

-"poop out" no longer feel effect of drugs

-Fluoxetine/ Prozac

-Sertraline/ Zoloft

-Paroxatine/ Paxil

-Fluvoxamine/ Luvox (not FDA)

-Citalopram/ Celexa

-Escitalopram/ Lexapro

2 solutions to side effect problems of SSRIs

1. drugs that block reuptake of NE and/or DA (with or without 5HT)

2. SSRI + 5HT_2a antagonists

-since 5HT2a mediates side effects- add component that blocks this receptor

- diff from classic TCAs cause no adrenergic, cholinergic or histaminergic blockade

Velafaxine

-generic

-blocks

Effexor

-blocks reuptake of 5HT & NE

-possible solution to side effects

Bupropion

-generic

-blocks

Wellbutrin or Zyban

DA & NE reuptake blocker

- no sexual dysfunction side effect (possible solution to SSRIs side effects)

Nefazodone

-generic

-blocks

Serzone

-blocks 5HT2a

-possible solution to SSRIs side effects

- MAO A: metabolizes 5HT, NE, tyramine, tryptamine

-MAO B: metabolizes DA, phenethylamine, benzylamine, tyramine, tryptamine

Original MAOIs were irreversible

-attached to enzyme permanently- new enzyme had to synthesize for return of activity

-MAOIs are metabolized by an intermediate agent that binds to MAO

-takes 10-14 days for MAO to return to normal after MAOIs are stopped (advised patients to not take any other meds even after stopping)

-Phenelzine- Nardil

-Traylcypromine- Parnate

9Isocarboxazid- Marplan

Deprenyl (Selegiline)

Selective MAO B inhibitor

-patch approved for depression

-doesn't require diet restriction, goes right into blood

-Tyramine from diet may increase blood pressure

-MAO A normally metabolizes this but is blocked by MAOIs

-diet restrictions needed to limit tyramine w/ MAOIs, reversible would stop the toxicity

RIMAs

eg.

Reversible Inhibitors of MAO

-eliminates problem of dietary/med restrictions

-tyramine or other amine would push RIMA off MAO

eg. Moclobemide

Befloxatone

Teloxantrone

Brofaromine

1. all AD are equally effective in tx of depression

2. 70% of patients will show improvement

3. meds differ in their side effects/ safety/easy of administration

4. cyclic ADs differ in chemical structure (3 rings tricyclic, newer have more heterocyclic, latest may not have ring structure)

-not clinically sig

2 things making drg tx for depression more complex then psychosis

1. diagnosis is more difficult, stigmas

2. tx for unipolar is diff than bipolar, AD to bilor can cause mania,  un/bi differ in response to mood stablilizing drugs

1. likely vs. unlikely (some rare)

2. uncomfortable vs dangerous (most unpleasant but safe)

3. tolerance may develop (start low and go slow)

4. ways to diminish w/ other drugs or Rx

blood levels with AD

-used with..

-important bc (4)

- Used w/ TCAs, antipsychotics, lithium, anticonvulsants

imp bc.

1. index of metabolism (30x diff b/ ppl for the same dose, blood level tells how quickly ind is getting rid of drug

2. shows therapeutic windown when drug is working

3. can tell if patient is taking meds

-determine right dose for therapy vs side effects

Experiment testing ADs

Effectiveness (real world) study

-mod to severe depression

- over 75% had recurrent/chronic dep

mean length of illness=15.5 yrs

Results

-started w/ citalopram (celexa) (avg 41.8 mg/day)

-about 30% remission

-about 47% responded

-about 6.7 weeks until remission

-patients offered 7 options (4 new meds or 3 augmentations)

-about 50% achieved remission after step 2

-Total time for remission 10-12 weeks

Non responders moved to 3, then 4

1. 67% cumulative remission rate after all 4 levels
2. relapse rates higher and time to relapse shorter for those entering more tx steps
3. Lots of patients left at each step
4. Remission had better prognosis then only responders

1. decrease side effect

2. reduce cog deficits

3. faster onset

4. efficacy in refractory patients (help more ppl)

5. get more ppl into remission

1. serotonin Transporter (SERT)

2. glutamate

3. Peptides

4. 2nd messengers

5. Neurogenic theory of depression

-abnormal devleopment of transporters might predispose depression (genetic causes

-might lead to therapies for AD nonresponders (improve their transporters)

1. non-competitive NMDA antag (ketamine, memantine)

-AP action in animals

-clinical trial of Ketamine had rebound AD effect

2. Glycine site- natural substance that helps glutamate affect receptor

3. AMPA/KAINATE

-AP action in animals

-might be good AD w/ no cog dysfunction

4. Metaboltropic glutamate receptors (mGluRs)

-group II and III- inhibit endogenous glutamate release (AD effect in rodents)

mGluR7

-most widely distributed auto receptor in brain

-glutamate hits this and stops further release

-negative feedback limits glutamate release, possible AD

1. Tachykinins (Neurokinins and Supstance P- SP)

2. Corticotrophin (CRF/CRH)- stress hormone

NK1- SP

NK2- Neurokinin A

NK3-neurokinin B

-SP receptors are used in stress (pain, vomiting, asthma, migraing, inflammatory bowel)

1. located in CNS site for stress

2. acute & chronic stressors increase SP

3. chronic AD tx reduce SP

4. depressed patients have higher levels of SP in plasma and CSF

5. Saredutant (antagonist) now in clinical trials

corticotrophin releasing factor/hormone

hypothalamus-CRF-> pituitary gland -ACTH->adrenal cortex -glucocorticoid/cortisol-> activates stress response

-when cortisol levels increase it sends neg feedback to hypothalamus and stops releasing,depressed patients neg feedback loop doesn't work and there is too much cortisol

Brain Derived Neurotrophic Factor- protects your brain from stress, helps w/ learning, memory, and neuronal development

CREB turns on genes that make BDNF

1. patients taking AD have increased CREB in temporal cortex when they die compared to unmedicated patients

2. Depressed patients less responsive to CREB activation

3. CREB activation greater for ppl responding to therapy (psychotherapy too)

neurogenic Theory

evidence

-suggests that altered neurogenesis (birth and survival of new neurons) relates to depression, Depression kills brain

Evidence: smaller hippocampus in depressed patients

Hippocampus is implicated in .. (3)

-evidence for

-hippocampus implicated in cognition, HPA control, and anxiety

Evidence for neurogenic theory:

-50% of depressed patients have dysfunctional HPA (cortisol) regulation

-activation of HPA axis w/ too much glucocorticoid for too long inhibits adult neurogenesis in hippocampus

1. increase rate of new cell birth

2. increase neurons that survive

3. AD tx blocks effects of stress normalizes neurogenesis) in adult hippocampus)

-changes consistent w/ time course of AD effect

1. acute & chronic stress downregulates BdNF (cortisol decreases BDNF expression)
2. chronic AD increases BdNF expression in rats (time course same as clinical delay)
3. postmortem depressed patients have inc BDNF expression if on AD and decreased in hippocampus if suicide
4. serum levles (blood levels) of BDNF dec in depressed patients and is reversed w/ AD

1. no direct evidence that loss of endogenous BDNF or reduced BDNF signaling produceses dep or impairs effect of AD

2. conflicting research results

3. diff effects of BDNF in diff brain areas

-increase as number of episodes increases

50%- 1 episode

70- 2 episodes

90- 3 episodes

-mild disorder, psychotic & melancholic features absent= psychotherapy best

-severe cases= AD best

-moderate= both