Depression

1
Depression
A stress-induced, reversible, structural disorder
of the brain, involving neuronal atrophy and
neuronal loss secondary to reduced expression of
certain neurotrophic factors that are essential
to maintenance of neuronal health and survival.
2
Causes of Depression

• Biological
• fluctuations in the levels of important
  neurotransmitters
• Serotonin
• Norephinephrine
• Genetic
• Environmental factors
• stressful situations
• ?????

3
Risk Factors for Depression
1. Gender serious depression 20-25 of women
and 12 of men (hormonal, stress levels,
more willing to seek treatment) 2. Marital
factors unhappily married, divorced, or
separated 3. Age First time 20-50 Especially
vulnerable gt65 4. Previous episode Half of
those who developed depression will experience it
again 5. Heredity
4
Types of Depression
1. Major depressive disorder 2. Dysthymic
disorder 3. Bipolar disorder 4. Cyclothymic
disorder 5. Mood disorder due to a general
medical condition 6. Substance-induced mood
disorder 7. Seasonal affective disorder
(SAD) 8. Postpartum depression 9. Premenstrual
dysphoric disorder
5
Facts about Depression
1. Major depression is the leading cause of
disability in US 2. Depression affects 10 of
population, or 12 million Americans per year 3.
Economic cost 30 billion/year 4. 2/3 of those
who are depressed dont seek treatment 5.
80-90 of those that seek treatment can feel
better within a few weeks
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Signal Transduction at Chemical Synapses
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The Players-1 Serotonin (5-hydroxytryptamine,
5-HT)
Synthesized CNS Importance regulation of body
temperature, mood, sleep, vomiting, sexuality,
appetite, anger, and aggression Low levels of
serotonin have been associated with depression,
migraine, irritable bowel syndrome, bipolar
disorder, and anxiety disorders 5-HT receptors
5HT1-5HT7, subtypes 5HT1A-B, 5HT1D-F, 5HT2A-C,
5HT5A-B Examples of agonist therapy
anti-migrane (5HT1D), stimulation of GIT motility
(5HT4) Example of antagonist therapy
anti-emetics (5HT3)
8
5-HT Receptors 5-HT3 is a 4 TM ligand gated ion
channel, all others are G-protein coupled 7 TM
receptors that activate an intracellular second
messenger cascade G-protein-coupled receptors
5-HT
9
The Players-2 Norepinephrine (noradrenaline)
Released CNS Importance controls alertness,
arousal Low levels of norepinephrine have been
associated with depression, attention-deficit/hyp
eractivity disorder Norepinephrine receptors a
and b adrenoreceptors
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Norephinephrine Receptors a and b adrenergic
receptors G-protein-coupled receptors
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adrenergic
Tissue distribution
Heart muscle b1 adrenergic receptors Fat
cells b3 adrenergic receptors Bronchial
muscle a1 b2 adrenergic receptors GI-tract
a1, a2 b2 adrenergic receptors
Clinical uses
b2 agonists asthma a1 agonists nasal
decongestants and with local anesthetics a2
agonists glaucoma, hypertension, pain a1
antagonists hypertension a2 antagonists
depression b1 antagonists slow heart rate and
reduce force of contraction
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Signal Transduction at Chemical Synapses
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Model for mechanism of action of antidepressants

• Short term
• increase 5-HT, NE
• Long term
• ?function and expression of their receptors
• ?cAMP signal transduction pathway
• ? expression and function of CREB and BDNF

DFosB despair-reducing protein transcription
factor that regulates the activity of multiple
genes. (Neuron, 2007, 55, 289)
14
Treatments-1
Monoamine oxidase inhibitors (MAOI) irreversible
inhibitors 1950-60s MAO enzyme responsible
for metabolism of dopamine, norepinephrine,
5-HT 2 forms MAO-A antidepressant
activities MAO-B side effects Types of
MAOIs 1. irreversible, nonselective
(iproniazid, isocarboxazid) 2. irreversible,
selective (selegiline, rasagiline) 3.
reversible, selective (RIMAs reversible
inhibitors of MAO-A moclobemide)
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Treatments-1
Monoamine oxidase inhibitors (MAOI) Initial
problems potentially fatal interactions with
certain foods (containing tyramine cheese,
wine, beer, liver, some beans) and
meds Ways around this problem 2003 MAOI
transdermal skin patch (eldapril) eliminates
food/drug interactions Reversible
MAOIs Recent progress crystal structure of
MAO-B (not A, 70 sequence identity) (Edmondson,
et al. Current Medicinal Chemistry, 11, 15, 2004,
1983-1993)
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Treatments-1
Monoamine oxidase inhibitors (MAOI) Design
based on observation that the anti-TB drugs
isoniazid and iproniazid showed stimulant
properties in TB patients and inhibited MAO.
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Treatments-1
Monoamine oxidase inhibitors (MAOI)
Covalent bound FAD
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Treatments-1
Monoamine oxidase inhibitors (MAOI)
Mechanism
Ref Edmondson, et al. Current Medicinal
Chemistry, 11, 15, 2004, 1983-1993.
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Signal Transduction at Chemical Synapses
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Treatments-2
Tricyclic antidepressants (TCAs)
1950-60s norepinephrine and 5-HT reuptake
inhibitors Side effects tiredness, increased
hunger, dry mouth, blurry vision, constipation,
bladder problems, sexual problems,
dizziness Problem not selective nonspecific
block of 5-HT, NE, histamine, and acetylcholine
receptors slow onset of action, fatal if
overdose Examples imipramine, desipramine,
trimipramine
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Treatments-2
Tricyclic antidepressants (TCAs)
Design Imipramine isosteric extension of the
phenothiazines
Amitriptyline replacement of N with sp2 C
Doxepin isosteric replacement of C with an O
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Re-uptake proteins

• Serotonin reuptake (uptake, carrier, transporter)
  protein
• The gene that encodes the serotonin transporter
  is called solute carrier
• family 6 (neurotransmitter transporter,
  serotonin), member 4 (SLC6A4).
• Also called hSERT, 5-HTT, 5HTT, HTT, OCD1 and
  SERT.
• 12 TM spanning protein, in presynaptic neuron
  (near synaptic cleft) ion dependent pump

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Signal Transduction at Chemical Synapses
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Re-uptake proteins

• areas important for selective 5HT affinity are
  localized within TMs 1-3 and TMs 8-12. SERT has a
  common binding site for 5HT and many of its
  inhibitors.
• mutations found in SLC6A4, in some unrelated
  families with OCD, that lead to faulty
  transporter function and regulation

• NE reuptake (uptake, carrier, transporter)
  protein
• Belong to the GAT1/NET (GABA, NE) family of
  transport proteins
• 12 TM domains

2005 1.65A crystal structure of LeuTAA, a
bacterial homolog of the neurotransmitter
transporters was determined. 2007 crystal
structure bound to TCAs substrate and inhibitor
binding sites distinct, TCAs seal off molecular
passageway (Gouaux, 2007, Nature DOI
10.1038/nature06038), (Wang/Reith, 2007,
Science DOI 10.1126/science.1147614)
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Treatments-3
SNRI, SSRI selective norepinephrine (serotonine)
reuptake inhibitors 1990s Side effects
headache, nausea, nervousness and insomnia,
agitation, sexual problems Problems
dependency, slow onset of action Ex effexor
XR, lexapro, zoloft, prozac, wellbutrin
XL SSRIs What is known? 5-HT at 5-HT1
receptors antidepressant activities 5-HT2
receptors insomnia, anxiety, agitation, sexual
dysfunction 5-HT3 receptors nausea
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Treatments-3
SNRI, SSRI Design antihistamine derivatives to
selectively target NE and 5-HT uptake. 1971
Zimelidine, 1st patented 1988 Prozac, Eli
Lilly, 1st FDA approved.
Theres the immediate action of the medication,
which leads to some black box we dont know
anything about, which leads to a cure. (Alan
Frazer, prozac, CE News, 6/05)
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Treatments-4

• Dual action antidepressants idea action at 2
  different synaptic sites may
• improve or maintain efficacy while limiting side
  effects.
• Examples
• Serzone 5-HT2 blockade and 5-HT and NE reuptake
  inhibitor. Problems liver failure insomnia,
  anxiety, agitation, sexual dysfunction
• Mirtazepine (1997) 5-HT2, 5-HT3, and histamine
  receptor blockade and
• 5-HT and NE reuptake inhibitor. Problems
  drowsiness, weight gain.
• nausea

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Market
2006 Top 20 Brand-Name Drugs 6 Effexor XR,
Wyteth, 2.25 billion. Serotonin reuptake
inhibitor 10 Lexapro, Forest, 2.10 billion.
Serotonin selective reuptake inhibitor 15
Zoloft, Pfizer, 1.77 billion. Serotonin
selective reuptake inhibitor 16 Wellbutrin XL,
GSK, 1.67 billion. 5-HT and dopamine reuptake
inhibitor Plus 3 others for schizophrenia and
bipolar disorder
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Model for mechanism of action of antidepressants

• Short term
• increase 5-HT, NE
• Long term
• ?function and expression of their receptors
• ?cAMP signal transduction pathway
• ? expression and function of CREB and BDNF

DFosB despair-reducing protein transcription
factor that regulates the activity of multiple
genes. (Neuron, 2007, 55, 289)
30
Problems with the current theory of depression-
action at monoaminergic synapses
1. Blockade of biogenic amine reuptake is
established within hours, but antidepressant
effects typically requires administration of the
drugs for at least 7-14 days. 2. Antidepressant
drugs such as iprindole and bupropion are, at
best, weak inhibitors of monoamine uptake 3.
Several potent reuptake inhibitors, most notably
cocaine and amphetamine, do not produce
antidepressant effects
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Signal Transduction at Chemical Synapses
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iGluRs and Glutamate

• Glutamate
• Major fast excitatory neurotransmitter in the CNS
• iGluRs have integral roles in
• Cognition and memory
• Development
• Neural plasticity
• Mis-regulation of iGluRs has implications in
• Ischaemic stroke
• Schizophrenia
• Epilepsy
• Alzheimers, Huntingtons, and Parkinsons
  disease

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iGluR Family Tree
iGluR
Non-NMDA
NMDA
NR1-(1-4) and NR2-(A,B,C,D) subunits
AMPA
Kainate
AMPA
GluR(1,2,3,4) subunits
GluR(5-7), KA(1-2) subunits
NMDA N-methyl-D-aspartate AMPA
amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid Kainate 2-carboxy-3-carboxymethyl-4-isoprope
nylpyrrolidine
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Antidepressants Binding to iGluRs

TERTIARY TCAs
Trimipramine
Imipramine
SECONDARY TCAs
Nortriptyline
Maprotiline
Desipramine
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Antidepressants Not Binding to iGluRs


SSRI
Fluoxetine