1. CHEM E-120 Harvard University Extension School
Disorders of Mood and Behavior
Depression
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2. Clinical Aspects of Mood Disorders
Mood disorders are determined based on diagnostic criteria from DSM-IV published by the
American Psychiatric Association.
Mood Episode (acute)
Major Depressive Episode
Manic Episode
Mixed Episode
Hypomanic Episode
Mood Disorders (chronic)
Depressive Disorders
Bipolar Disorders
Mood Disorder due to a General Medical Condition
Substance-Induced Mood Disorder
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3. Clinical - Major Depressive Episode
Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure.
(1) depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). Note: In children and adolescents, can be irritable mood.
(2) markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others)
(3) significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. Note: In children, consider failure to make expected weight gains.
(4) insomnia or hypersomnia nearly every day
(5) psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down)
(6) fatigue or loss of energy nearly every day
(7) feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick)
(8) diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others)
(9) recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide
C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of function
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4. Clinical Aspects of Depression
Major Depressive Disorder, Single Episode 296.2x (unipolar depression)
Presence of a single Major Depressive Episode
The Major Depressive Episode is not better accounted for by Schizoaffective Disorder
and is not superimposed on Schizophrenia, Schizophreniform Disorder, Delusional
Disorder, or Psychotic Disorder Not Otherwise Specified.
There has never been a Manic Episode, a Mixed Episode, or a Hypomanic Episode.
Major Depressive Disorder, Recurrent 296.3x (melancholia)
Presence of two or more Major Depressive Episodes. Note: To be considered separate
episodes, there must be an interval of at least 2 consecutive months in which criteria are
not met for a Major Depressive Episode.
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5. Clinical Aspects of Depression
Dysthymic Disorder 300.4
During a majority of days for 2 years or more, the patient reports depressed mood or appears
depressed to others for most of the day. When depressed, the patient has 2 or more of:
Appetite decreased or increased
Sleep decreased or increased
Fatigue or low energy
Poor self-image
Decreased concentration and decisiveness
Feels hopeless or pessimistic
During this 2 year period, the above symptoms are never absent longer than 2 consecutive months.
During the first 2 years of this syndrome, the patient has not had a Major Depressive Episode.
These symptoms must result in clinically significant distress or impairment in social, occupational, academic, or other major areas of functioning (APA, 2000).
Treatment
produce symptomatic improvement (response)
symptom resolution and optimal functioning (remission)
prevent relapse or recurrence
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6. Nervous System Central Nervous System (CNS) Brain Spinal cord
Processes and stores motor and sensory information
Important regions of the brain involved in psychiatric disorders
Cerebral Cortex - Frontal lobe, motor cortex
Limbic Lobe - drives, emotions, memory
Hippocampus, Amygdala
Basal ganglia (movement control)
Caudate nucleus
Lenticular nucleus
putamen
globus pallidus
Thalamus - functions as a relay to cortex
Hypothalamus- controls autonomic function
Peripheral Nervous System (PNS)
Nerve network from (efferent) and to (afferent) the spinal cord, connects CNS to muscles and organs
Both afferent and efferent come from French, evolved from Latin (the basis of many terms in medicine and biology) for the terms, respectively, ad ferens (Latin verb ferre: carry), meaning carrying into, and ex ferens, meaning carrying away.
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7. Limbic System Amygdala and hippocampus Hypothalamus
A group of interconnected structures (cells) that mediate emotions, learning and memory. Structures are interposed between the hypothalamus and neocortex.
Amygdala and hippocampus
Primitive parts of the brain involved in behavioral control
Amygdala and its neural connections are centrally involved in emotional experiences and responses. Receives specific sensory inputs of sight, sound, touch, smell, and taste, and more general sensory inputs of levels of physical and emotional comfort and discomfort.
Hippocampus has a primary role in some forms of learning and memory.
Hypothalamus
Connecting point in pathways concerned with autonomic, endocrine, emotional, and somatic functions that are designed to maintain homeostasis. Function extends into drives and emotional behaviors.
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8. Neuropathology of Depression
Neuroimaging studies detected structural and functional abnormalities in
prefrontal cortex, hippocampus, amygdala, stiratum, and thalamus.
Prefrontal lobe dysfunction
fMRI has shown dysfunction in prefrontal cortex and basal ganglia
Interconnected neural circuit of anterior cingulate, ventral sriatum, thalamus and hippocampus.
Patients with Parkinson’s or Huntington’s Disease have elevated levels of depression – basal ganglia dysfunction
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9. Depression Neurocircuitary Cortex Cortex HC Am Serotonin
Thalumus
Putamen
NuAcc HC
HYPTh
VTA Am
Locus coeruleus
Raphe nuclei
Serotonin
Norepinephrine
Glutaminergic
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10. Imaging
PET and SPECT require radioisotopes
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11. Imaging
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12. Imaging - fMRI
Functional MRI produces images by applying a magnetic field and detecting radiofrequency energy from the protons in water molecules.
However, functional MRI exploits two additional facts,
• Biologically, the more oxygen that cells in a region utilize, the more oxygen-carrying hemoglobin molecules will be found in the blood vessels responsible for supplying them.
• Physically, hemoglobin molecules that have oxygen molecules attached to them and those that do not exert measurably different effects on the magnetic properties of surrounding tissues.
By tuning the magnets and energy pulses of the MRI machine to capture these differences, researchers produce images in which differences in oxygen content show up as variations in tone or color. This is called blood oxygen level dependent, or BOLD, contrast.
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13. Imaging - fMRI
High brain activity require more oxygen and produce a stronger BOLD signal than areas of low brain activity
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14. PET
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15. PET
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16. Annu. Rev. Neurosci, 2009, 32, 57-74
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17. High level brain activity = high glucose uptake – taken to reflect neuronal activity
measure uptake of [18F]-2-fluoro-2-deoxyglucose, 18F t1/2 = 110 minutes
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18. Neurochemistry of Depression - Serotonin
Decrease in serotonin levels in brainstem and in CSF
Lower number of serotonin transporter and receptor binding sites in brain stem (SPECT), cerebral cortex (postmortem), midbrain raphe and hippocampus (PET)
5-HT1A receptors downregulated in midbrain raphe and hippocampus, 5-HT2A
receptors upregulated in frontal cortex
Relapse of depression upon depletion of tryptophan (precursor of serotonin)
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19. Neurochemistry of Depression - Norepinephrine
Catecholamine depletors (reserpine) induce major depression
Inhibition of tyrosine hydroxylase induces relapse of depression in patients treated with norepinephrine reuptale inhibitors
Reduced levels of metabolites have been detected in depressed patients.
Downregulation of -adrenergic and maybe 2-adrenergic receptors
Greater corticol levels of norepinephrine, reduced high-affinity 1-adrenergic
binding, fewer noradrenergic neurons
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20. Hypotheses of Depression
Monoamine Hypothesis: Depression results from a deficiency of
serotonin (5-HT) and/or norepinephrine (NE)
Receptor Sensitivity Hypothesis: loss of sensitivity to 5-HT and NE in post-synaptic receptors, onset of hypersensitivity and upregulation modulated by antidepressants - normalization of receptor sensitivity
Permissive Hypothesis: imbalance in the relative concentrations of 5-HT
and NE. Loss of NE perturbs serotoninergic balance leading to depression
Hormonal Hypothesis: perturbation of hypothalamus-pituitary-adrenal axis (HPA) can affect 5-HT and NE neuronal release. (Neurochem Res 2008, 33, 691, Trends in Neuroscience 2008, 31, 464)
GABA Hypothesis: reduced levels of GABA (Molecular Psychiatry , 721–737)
Glutamate Hypothesis: abnormal levels of glutamate (Nature Drug Discovery 2008, 7, 426)
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21. Neurotransmitter Deficiency Syndromes and Interactions
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22. Clinical Studies on GABA
Molecular Psychiatry 2003, 8,
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23. Glutamatergic System Alterations Nature Rev DD 2008, 7, 426
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24. Potential Targets of Interest
Postsynaptic
ion concentration
second messenger (protein synthesis)
mGlu1/5 (controls Ca2+)
NMDA ionotropic (controls Ca2+)
AMPA ionotropic (controls Na+)
β-adrenergic second messenger system
α1-adrenergic (NE) “
5-HT2
5-HT1A “
5-HT4 “
5-HT5 “
5-HT7 “
D1 “
D2 “
D5 “
Presynaptic
neurotransmitter modulation
5-HT1A GPCR
α2-adrenergic (NE)
mGlu2 GPCR glutamate
NMPA glutamate receptor
MOA enzyme
monoamine transporters
DAT
NET
SERT
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25. Tricyclic Antidepressants (TCA)
First developed in imipramine (Tofranil)
NET reuptake inhibitor
Similar is structure to Chlorpromazine
S replaces CH2-CH2
Bioisosteric replacement
antidepressant
antipsychotic
TCA’s bind to multiple receptors. Imipramine has similar efficacy at muscarinic, serotonergic, -adrenergic, and H1 receptors and SERT & NET
Tricyclic ring system - promiscous binder
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26. Reuptake Inhibitors
Adverse side effects of TCA’s, coupled with growing evidence of the importance of the monoamine hypothesis and efficacy of reuptake inhibitors lead to this approach being the one of choice in the 1970’s.
3 approaches
SSRI - selective serotonin reuptake inhibitors
Increase the concentration of 5-HT in the synapse by targeting the inhibition of serotonin reuptake transporters (SERT) on the presynaptic neuron
SNRI - selective norepinephrine reuptake inhibitors
Increase the concentration of NE in the synapse by targeting the inhibition of norepinephrine reuptake transporters (NET) on the presynaptic neuron
NSRI - nonselective SERT/NET
Increase the concentration of both NE and 5-HT
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27. Cell Surface Proteins - Transporter
SERT has ~ 50%
homology with DAT/NET
SERT located on
serotonergic neurons
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28. Reuptake Inhibitors SARI – 5-HT2 antagonist/SSRI
Foye p 555
SARI – 5-HT2 antagonist/SSRI
NaSSAs – presynaptic α2-adrenergic antagonists
5-HT2, 5-HT3 antagonist
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29. Serotonin Reuptake Inhibitors
Antihistimine drugs were found to inhibit 5-HT reuptake. Served as a lead series of compounds for optimization.
move pyridine N
p-Br
Z-zimeldine (Zemid) first SSRI
metabolite Norzimeldine 15x active
E-zimeldine SERT/NET
E-Norzimeldine NET inhibitor
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30. Serotonin Reuptake Inhibitors
Mechanism of action
SSRI’s bind to SERT (~70-80% efficacy), inhibiting the reuptake of serotonin thus increasing the concentration of 5-HT in the synapse.
Increase in 5-HT overactivates postsynaptic receptors leading to downregulation of pre/post synaptic receptors and SERT (15 days) and a decrease in 5-HT production.
(Receptor Sensitivity Hypothesis: loss of sensitivity to 5-HT and NE in post-synaptic receptors, onset of hypersensitivity and upregulation modulated by antidepressants - normalization of receptor sensitivity)
This plasticity of receptors and 5-HT is thought to produce the antidepressant effect - delayed action of SSRI’S
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31. Inhibition of Reuptake
IC50 of a drug is determined from competition experiments where the displacement of a strong binding ligand (usually radioactive) by a drug is measured.
[3H]-dopamine ([3H]-DA), [3H]-serotonin ([3H]-5-HT), [3H]-norepinephrine ([3H]-NE)
Incubate cloned transporters stably expressed in cells with a quantity of the radiolabled neurotransmitter and the drug.
Kd= dissociation constant of the radiolabled ligand
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32. SSRI - Fluoxetine Ki (nM) SERT 0.810 NET 244 DAT 3,600
Life Sciences 1995, 57, 411
1974, 15, 471
1997, 61, 1203
Ki (nM)
SERT 0.810
NET 244
DAT 3,600
rat synaptosomes Ki = 21 nM nM
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33. SSRI - Fluoxetine - SAR Phenoxy ring modified Synthetically easier
SERT
Ortho substitution not
tolerated
Para substitution favors
SERT over NET
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34. SSRI - Fluoxetine - Selectivity
TCA
TCA
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35. SSRI Fluoxetine Metabolism
Renal: 80% excreted in the urine (11.6% fluoxetine, 7.4% fluoxetine glucuronide, 6.8% norfluoxetine, 8.2% norfluoxetine glucuronide, > 20% hippuric acid, 46% other) .
S 20 nM
R 268 nM
Substrate of CYP1A2 (minor), 2B6 (minor), 2C9 (major), 2C19 (minor), 2D6 (major), 2E1 (minor), 3A4 (minor); Inhibits CYP1A2 (moderate), 2B6 (weak), 2C9 (weak), 2C19 (moderate)
2D6 (strong), 3A4 (weak)
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36. SSRI - Sertraline (Zoloft)
Ki (nM) Prozac Zoloft
SERT
NET
DAT 3,
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37. SSRI - Sertraline (Zoloft)
SAR trans series
J. Med. Chem. 1984, 27, 1508
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38. SSRI - Sertraline (Zoloft)
SAR cis series
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39. SSRI - Zoloft Affects of stereochemistry on bioactivity
Zoloft® (Sertraline)
SSRI - antidepressant
Pfizer 2004 $3.6B
1S, 4S
1R,4R
1R,4S
1S,4R
Inhibition of monoamine uptake in rat brain synaptosomes IC50 (M)
Transporter
cis racemate
1S,4S
1R,4R
trans racemate
1R,4S
1S,4R
Dopamine
0.52
1.3
0.32
0.06
0.044
0.27
Serotonin
0.074
0.46
0.05
0.039
0.47
Norepinephrine
0.72
1.2
0.30
0.022
0.01
J. Med. Chem. 1984, 27, 1508
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40. SSRI Sertraline Metabolism
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41. SSRI - Zoloft Process Chemistry
Three separate steps without isolating intermediates. Process changes reduce solvent requirements to 6,000 gal from 60,000 gal per ton of sertraline.
Eliminates 440 metric tons of titanium dioxide-methylamine hydrochloride salt waste, 150 metric tons of 35% hydrochloric acid waste, and 100 metric tons of 50% sodium hydroxide waste per year.
Overall yield doubled to 37% and raw materials cut up to 60%
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42. SSRI – In Vivo 5-HT Concentrations
Life Sciences 1995, 57, 411
TCA
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43. SNRI- selective norepinephrine reuptake inhibitors
Affect the noradrenergic system. Increase levels of NE. TCA tend to be NET selective though they bind well to SERT
Desipramine
Actual active drug
Imipramine
antidepressant
Weak antidepressant
% Bioavailibity
% protein binding
Plasma t1/2
Vd (l/kg)
[Plasma]
NET/SERT/DAT
K1 (nM)
Imipramine
hrs
>180 ng/mL
37/1.4/8300
desimipramine
hrs
145 ng/mL
0.83/17.7/3200
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44. SNRI - SAR
Ki (nM)
NET
SERT
DAT
D2 and 5-HT2 antagonist
properties - antipsychotic
Goodman and Gilman 9th p 437
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45. SNRI - Non TCA
(R)
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46. SNRI - Talopram
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47. SNRI - Talopram SERT NET J. Med. Chem., 2008, 51 (10), 3045-3048
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48. SSNRI - Dual selective serotonin norepinephrine reuptake inhibitors
The Art of Drug Synthesis Chapter
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49. Effexor Cymbalta molecular weight 277 246 297 ClogP 2.9 1.4 4.3
HBD
HBA
tPSA
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50. Descriptors of Molecules - Electrostatic Charge
molecular electrostatic potential map
dot cloud – size of cloud represents
amount of charge
PSA – polar surface area

51. Dopamine and NE dual reuptake inhibitor - Bupropion
1966 Discovered by Burroughs (GSK)
1985 FDA approval Major Depressive Disorder
1986 Withdrawal of drug 1986 due to seizures at mg
1989 Reintroduced at maximum dosage of 450 mg/day
Ki (μM)
NET 1.4
SERT 45
DAT 2.8
Nat. Rev. Neurosci 2003, 4, 13
H1 6.7
1 4.55
M 40
Goodman & Gilman Chapter 17
oral bioavailability 5-20%
Protein Binding 80%
Elimination t1/2 21 hrs
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52. Dopamine and NE reuptake inhibitor - Bupropion
Bupropion is extensively metabolized to active metabolites
IC50 (μM)
Drug NET DAT
rac Bupropion
Hydroxybupropion >10 1.7
S,S-hydroxybupropion
S,R-hydroxybupropion >10 >10
(+/-) Bupropion
(S)-(+)-bupropion
(R)-(-)-bupropion
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53. Learned helplessness in rats
Despair swim test
PURPOSE AND RATIONALE
Behavioral despair was proposed as a model to test for antidepressant activity by Porsolt et al. (1977, 1978). It was suggested that mice or rats forced to swim in a restricted space from which they cannot escape are induced to a characteristic behavior of immobility. This behavior reflects a state of despair which can reduced by several agents which are therapeutically effective in human depression. Antidepressant drugs, but also stimulants like amphetamine and caffeine, reduce duration of immobility. Dose-responses can be evaluated.
Learned helplessness in rats
Animals exposed to inescapable and unavoidable electric shocks in one situation later fail to escape shock in a different situation when escape is possible. This phenomenon was evaluated as a potential animal model of depression. A drug is considered to be effective, if the learned helplessness is reduced and the number of failures to escape is decreased.
Tail suspension test in mice
The “tail suspension test” has been described as a facile means of evaluating potential antidepressants. The immobility displayed by rodents when subjected to an unavoidable and inescapable stress has been hypothesized to reflect behavioral despair which in turn may reflect depressive disorders in humans. Clinically effective antidepressants reduce the immobility that mice display after active and unsuccessful attempts to escape when suspended by the tail.
For the test the mice are suspended on the edge of a shelf 58 cm above a table top by adhesive tape placed approximately 1 cm from the tip of the tail. The duration of immobility is recorded for a period of 5 min. Mice are considered immobile when they hang passively and completely motionless for at least 1 min.
Drug discovery and evaluation : pharmacological assays / H. Gerhard Vogel …2nd ed. 2002
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54. Bupropion and metabolites – forced swim test
(S,R-hydroxybupropion)
rac hydroxybupropion
IC50 (μM)
NET DAT
rac Bupropion
Hydroxybupropion >
S,S-hydroxybupropion
S,R-hydroxybupropion >10 >10
reduction of
immobility
time
Δ Bupropion
 (S,S-hydroxybupropion)
Mol Pharm 2004, 66, 675
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55. DRUG METABOLISM AND DISPOSITION 2000, 28:1176–1183
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56. 5-HT1A/B/D antagonists J. Med. Chem. 2008, 51, 2887–2890
Discovery of Potent, Orally Bioavailable,
Selective 5-HT1A/B/D Receptor Antagonists
Psychiatry Centre of Excellence for Drug
Discovery and Molecular Discovery Research,
GlaxoSmithKline
Abstract: 5-HT1 receptor antagonists have been discovered with good selectivity over the 5-HT transporter. This is the first report of highly potent, selective ligands for the 5-HT1A/B/D receptors with low intrinsic activity, which represent a useful set of molecules for further understanding the roles of the 5-HT1 receptor subtypes and providing new approaches for the treatment of depression.
Trazodone (1981)
5-HT2A antagonist
5-HT reuptake inhibitor
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57. Receptor/Drug - Antagonists
A competitive antagonist will compete with the ligand (agonist) for binding to the binding site, upon binding, no effect is observed.
concentration ratio
pA2 = -log[B]r=2
B = [antagonist] where the
[agonist] must be doubled
to obtain an equal response
~ 1000 fold increase in [A]
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58. 5-HT1A/B/D antagonists
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59. 5-HT1A/B/D antagonists
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60. 5-HT1A/B/D antagonist – GSK 163090
Trazodone (1981)
5-HT2A antagonist
5-HT reuptake inhibitor
GSK163090
Currently in Phase 2 clinical trials
Compound 18
pKi
clogP
t1/2 hrs
CNS Br/Bl
Fpo %
5-HT1A
5-HT1B
5-HT1D 18
8.6
8.7
9.3
3.5
0.6
0.2
GSK163090
9.4
8.5
9.7
3.2
0.5 58
5.3
63 (monkey)
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61. Combination of Antidepressant Medications From Treatment Initiation for Major Depressive Disorder: A Double-Blind Randomized Study (Am J. Psychiatry 2010, 167, 281)
“response to a single antidepressant medication, classically measured as an attenuation of 50% or more in the intensity of depressive symptoms, is generally obtained in about 50%–75% of patients with a first trial”
“Remission rates are generally around 30% with a single agent”
score of ≤7 HAM-D test
(start of ~22)
Patients (N=105) meeting DSM-IV criteria for major depressive disorder were randomly assigned to receive, from treatment initiation, either fluoxetine monotherapy (20 mg/day) or mirtazapine (30 mg/day) in combination with fluoxetine (20 mg/day), venlafaxine (225 mg/ day titrated in 14 days), or bupropion (150 mg/day) for 6 weeks. The primary outcome measure was the Hamilton Depression Rating Scale (HAM-D) score.
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