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CHEM E-120Harvard University Extension School

Disorders of Mood and BehaviorDepression2/9/2011

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Clinical Aspects of Mood Disorders

Mood disorders are determined based on diagnostic criteria from DSM-IV published by theAmerican Psychiatric Association.

Mood Episode (acute)

Major Depressive EpisodeManic EpisodeMixed EpisodeHypomanic Episode

Mood Disorders (chronic)

Depressive DisordersBipolar DisordersMood Disorder due to a General Medical ConditionSubstance-Induced Mood Disorder

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Clinical - Major Depressive EpisodeFive (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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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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Clinical Aspects of DepressionDysthymic Disorder 300.4

During a majority of days for 2 years or more, the patient reports depressed mood or appearsdepressed to others for most of the day. When depressed, the patient has 2 or more of:

Appetite decreased or increasedSleep decreased or increasedFatigue or low energyPoor self-imageDecreased concentration and decisivenessFeels 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)

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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

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Limbic System

• 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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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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VTAAmHYPTh

HCThalumus

Putamen NuAcc

SerotoninNorepinephrineGlutaminergic

Cortex

Cortex

Raphe nuclei

Locus coeruleus

DepressionNeurocircuitary

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Imaging

PET and SPECT require radioisotopes

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Imaging

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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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Imaging - fMRI

High brain activity require more oxygen and produce a stronger BOLD signal than areas of low brain activity

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PET

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PET

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Annu. Rev. Neurosci, 2009, 32, 57-742/9/2011 CHEM E-120

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High level brain activity = high glucose uptake – taken to reflect neuronal activitymeasure uptake of [18F]-2-fluoro-2-deoxyglucose, 18F t1/2 = 110 minutes

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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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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 receptorsGreater corticol levels of norepinephrine, reduced high-affinity 1-adrenergicbinding, fewer noradrenergic neurons

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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-HTand 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 2003 8, 721–737)

Glutamate Hypothesis: abnormal levels of glutamate (Nature Drug Discovery 2008, 7, 426)

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Neurotransmitter Deficiency Syndromes and Interactions

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Clinical Studies on GABA

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Molecular Psychiatry 2003, 8, 721-737

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Glutamatergic System Alterations Nature Rev DD 2008, 7, 426

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Potential Targets of Interest

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Presynaptic

neurotransmitter modulation

5-HT1A GPCRα2-adrenergic (NE)mGlu2 GPCR glutamateNMPA glutamate receptorMOA enzymemonoamine transporters

DATNETSERT

Postsynaptic

ion concentrationsecond messenger (protein synthesis)

mGlu1/5 (controls Ca2+)NMDA ionotropic (controls Ca2+)AMPA ionotropic (controls Na+)β-adrenergic second messenger systemα1-adrenergic (NE) “5-HT2

5-HT1A “5-HT4 “5-HT5 “5-HT7 “D1 “D2 “D5 “2/9/2011 CHEM E-120

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Tricyclic Antidepressants (TCA)

First developed in 1958 - imipramine (Tofranil) NET reuptake inhibitor

Similar is structure to ChlorpromazineS 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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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 inhibitorsIncrease 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 inhibitorsIncrease the concentration of NE in the synapse by targeting the inhibition of norepinephrine reuptake transporters (NET) on the presynaptic neuron

NSRI - nonselective SERT/NETIncrease the concentration of both NE and 5-HT

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Cell Surface Proteins - Transporter

SERT has ~ 50%homology with DAT/NET

SERT located on serotonergic neurons

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Reuptake Inhibitors

Foye p 555

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SARI – 5-HT2 antagonist/SSRINaSSAs – presynaptic α2-adrenergic antagonists

5-HT2, 5-HT3 antagonist

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Serotonin Reuptake InhibitorsAntihistimine drugs were found to inhibit 5-HT reuptake. Served as a lead series of

compounds for optimization.

Z-zimeldine (Zemid) first SSRImetabolite Norzimeldine 15x active

move pyridine Np-Br

E-zimeldine SERT/NETE-Norzimeldine NET inhibitor

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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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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.

€

Ki =IC50

1+[L]totKd

Kd= dissociation constant of the radiolabled ligand

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SSRI - Fluoxetine

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 16 nM2/9/2011 CHEM E-120

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SSRI - Fluoxetine - SAR

Phenoxy ring modifiedSynthetically easier

SERTOrtho substitution nottoleratedPara substitution favorsSERT over NET

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SSRI - Fluoxetine - Selectivity

TCA

TCA2/9/2011 CHEM E-120

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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) .

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)

S 20 nMR 268 nM

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SSRI - Sertraline (Zoloft)

Ki (nM) Prozac Zoloft

SERT 0.810 0.293

NET 244 417

DAT 3,600 25

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SSRI - Sertraline (Zoloft)

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SAR trans seriesJ. Med. Chem. 1984, 27, 1508

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SSRI - Sertraline (Zoloft)

SAR cis series

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SSRI - Zoloft Affects of stereochemistry on bioactivity

Inhibition of monoamine uptake in rat brain synaptosomes IC50 (M)

1S, 4S 1R,4R 1R,4S 1S,4R

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 0.06 0.46 0.05 0.039 0.47

Norepinephrine 0.72 1.2 0.30 0.022 0.01 0.044

Zoloft® (Sertraline)SSRI - antidepressantPfizer 2004 $3.6B

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SSRI Sertraline Metabolism

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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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SSRI – In Vivo 5-HT Concentrations

TCA

Life Sciences 1995, 57, 411

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SNRI- selective norepinephrine reuptake inhibitorsAffect the noradrenergic system. Increase levels of NE. TCA tend to be NET selective though they bind well to SERT

Imipramineantidepressant

DesipramineActual active drug

Weak antidepressant

% Bioavailibity % protein binding

Plasma t1/2 Vd (l/kg) [Plasma] NET/SERT/DATK1 (nM)

Imipramine 29 - 77 76 - 95 9 - 24 hrs 15 - 30 >180 ng/mL 37/1.4/8300

desimipramine 60 - 70 73 - 90 14 - 62 hrs 22 - 59 145 ng/mL 0.83/17.7/3200

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SNRI - SAR

NET 1.40 4.35 0.83 11.1 16.1SERT 19.6 18.5 17.5 5900 58.5DAT 2130 1140 3200 1000 4350

Ki (nM)

Goodman and Gilman 9th p 437

D2 and 5-HT2 antagonistproperties - antipsychotic

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SNRI - Non TCA

(R)

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SNRI - Talopram

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SNRI - Talopram

SERT

NET

J. Med. Chem., 2008, 51 (10), 3045-3048

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SSNRI - Dual selective serotonin norepinephrine reuptake inhibitors

The Art of Drug Synthesis Chapter 14 2007

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molecular weight 277 246 297ClogP 2.9 1.4 4.3 HBD 1 1 1HBA 3 2 2 tPSA 32.7 46.3 21.3

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CymbaltaEffexor

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Descriptors of Molecules - Electrostatic Charge

molecular electrostatic potential map

PSA – polar surface areadot cloud – size of cloud representsamount of charge

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Dopamine and NE dual reuptake inhibitor - Bupropion

Ki (μM)

NET 1.4SERT 45DAT 2.8Nat. Rev. Neurosci 2003, 4, 13

H1 6.71 4.55M 40Goodman & Gilman Chapter 17

1966 Discovered by Burroughs (GSK)1985 FDA approval Major Depressive Disorder1986 Withdrawal of drug 1986 due to seizures at 400-600 mg1989 Reintroduced at maximum dosage of 450 mg/day

oral bioavailability 5-20%Protein Binding 80%Elimination t1/2 21 hrs

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Dopamine and NE reuptake inhibitor - Bupropion

Bupropion is extensively metabolized to active metabolites

IC50 (μM)Drug NET DAT

rac Bupropion 1.9 0.55 Hydroxybupropion >10 1.7S,S-hydroxybupropion 0.52 0.79S,R-hydroxybupropion >10 >10

(+/-) Bupropion 6.7 2.1 (S)-(+)-bupropion 4 2.3(R)-(-)-bupropion 10.5 4.2

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ClHN

O

OH Cl NH

O

OHCH3

2R,3R

Cl NH

O

OHCH3

2S,3S

Cl NH

O

OHCH3

2S,3R

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Despair swim testPURPOSE AND RATIONALEBehavioral 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 ratsPURPOSE AND RATIONALEAnimals 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 micePURPOSE AND RATIONALEThe “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. 20022/9/2011 CHEM E-120

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Bupropion and metabolites – forced swim test

(S,R-hydroxybupropion)

Δ Bupropion

rac hydroxybupropion

(S,S-hydroxybupropion)

reduction ofimmobilitytime

Mol Pharm 2004, 66, 675

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IC50 (μM)NET DAT

rac Bupropion 1.9 0.55 Hydroxybupropion >10 1.7S,S-hydroxybupropion 0.52 0.79S,R-hydroxybupropion >10 >10

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DRUG METABOLISM AND DISPOSITION 2000, 28:1176–11832/9/2011 CHEM E-120

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5-HT1A/B/D antagonists

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.

J. Med. Chem. 2008, 51, 2887–2890

Trazodone (1981) 5-HT2A antagonist5-HT reuptake inhibitor

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Receptor/Drug - AntagonistsA competitive antagonist will compete with the ligand (agonist) for binding to the binding site, upon binding, no effect is observed.

pA2 = -log[B]r=2

~ 1000 fold increase in [A]

concentration ratio

B = [antagonist] where the[agonist] must be doubledto obtain an equal response

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5-HT1A/B/D antagonists

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5-HT1A/B/D antagonists

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5-HT1A/B/D antagonist – GSK 163090

GSK163090Currently in Phase 2 clinical trials

Trazodone (1981) 5-HT2A antagonist5-HT reuptake inhibitor

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 3.5 3.2 0.5 58

5.3 63 (monkey)

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“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.

Combination of Antidepressant Medications From Treatment Initiation for Major Depressive Disorder: A Double-Blind Randomized Study (Am J. Psychiatry 2010, 167, 281)