660 likes | 996 Views
CHEM E-120 Harvard University Extension School. Disorders of Mood and Behavior Depression 2/2/2011. 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)
E N D
CHEM E-120Harvard University Extension School Disorders of Mood and Behavior Depression 2/2/2011
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
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
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.
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
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
Depression Neurocircuitary Cortex Cortex Thalumus Putamen NuAcc HC HYPTh VTA Am Locus coeruleus Raphe nuclei Serotonin Norepinephrine Glutaminergic
Imaging PET and SPECT require radioisotopes CHEM E-120
Imaging CHEM E-120
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. CHEM E-120
Imaging - fMRI High brain activity require more oxygen and produce a stronger BOLD signal than areas of low brain activity CHEM E-120
PET CHEM E-120
PET CHEM E-120
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
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)
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
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 2003 8, 721–737) Glutamate Hypothesis: abnormal levels of glutamate (Nature Drug Discovery 2008, 7, 426)
Clinical Studies on GABA Molecular Psychiatry 2003, 8, 721-737
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
Tricyclic Antidepressants (TCA) First developed in 1958 - 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
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
Cell Surface Proteins - Transporter SERT has ~ 50% homology with DAT/NET SERT located on serotonergic neurons CHEM E-120
Reuptake Inhibitors Foye p 555
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
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
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 CHEM E-120
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 nM
SSRI - Fluoxetine - SAR Phenoxy ring modified Synthetically easier SERT Ortho substitution not tolerated Para substitution favors SERT over NET
SSRI - Fluoxetine - Selectivity TCA TCA
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)
SSRI - Sertraline (Zoloft) Ki (nM) Prozac Zoloft SERT 0.810 0.293 NET 244 417 DAT 3,600 25
SSRI - Sertraline (Zoloft) SAR trans series
SSRI - Sertraline (Zoloft) SAR cis series
Zoloft® (Sertraline) SSRI - antidepressant Pfizer 2004 $3.6B SSRI - Zoloft Affects of stereochemistry on bioactivity 1S, 4S 1R,4R 1R,4S 1S,4R Inhibition of monoamine uptake in rat brain synaptosomes IC50 (M) J. Med. Chem. 1984, 27, 1508
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%
SSRI - Comparison Life Sciences 1995, 57, 411 TCA
SNRI 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
SNRI - SAR Ki (nM) NET 1.40 4.35 0.83 11.1 16.1 SERT 19.6 18.5 17.5 5900 58.5 DAT 2130 1140 3200 1000 4350 D2 and 5-HT2 antagonist properties - antipsychotic Goodman and Gilman 9th p 437
SNRI - Non TCA (R)
SNRI - Talopram SERT NET J. Med. Chem., 2008, 51 (10), 3045-3048
SSNRI Dual selective serotonin norepinephrine reuptake inhibitors. The Art of Drug Synthesis Chapter 14 2007
molecular weight 277 246 297 ClogP 2.9 1.4 4.3 HBD 1 1 1 HBA 3 2 2 tPSA 32.7 46.3 21.3
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 400-600 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 bioavialibility 5-20% Protein Binding 80% Elimination t1/2 21 hrs
Dopamine and NE reuptake inhibitor - Bupropion Bupropion is extensively metabolized to active metabolites IC50 (μM) Drug NETDAT rac Bupropion 1.9 0.55 Hydroxybupropion >10 1.7 S,S-hydroxybupropion 0.52 0.79 R,R-hydroxybupropion >10 >10 (+/-) Bupropion 6.7 2.1 (S)-(+)-bupropion 4 2.3 (R)-(-)-bupropion 10.5 4.2
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 PURPOSE AND RATIONALE 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 PURPOSE AND RATIONALE 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