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How do psychiatric drugs work? 1 1.Statement of the problem: Antispychotics, Antidepressants, Bipolar drugs 2.Lessons from nAChRS; 3. Pharmacokinetics.

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Presentation on theme: "How do psychiatric drugs work? 1 1.Statement of the problem: Antispychotics, Antidepressants, Bipolar drugs 2.Lessons from nAChRS; 3. Pharmacokinetics."— Presentation transcript:

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2 How do psychiatric drugs work? 1 1.Statement of the problem: Antispychotics, Antidepressants, Bipolar drugs 2.Lessons from nAChRS; 3. Pharmacokinetics 4. Detailed hypotheses: Antipsychotic drugs SSRI Antidepressant drugs “Fast” NMDA blocker antidepressants 5.Tests of “inside-out” mechanisms for psychiatric drugs Psychiatric drugs bind to classical targets within early exocytotic pathways: Therapeutic effects Biological Psychiatry, Dec 2012 Henry A. Lester, Julie M. Miwa, and Rahul Srinivasan

3 2 Disclaimer This session deals with psychiatric disease. Henry Lester is not a psychiatrist--not even a physician. Don’t change any medical treatment that you might now be receiving on the basis of these lectures. Don’t give any medical advice based on these lectures or problem sets.

4 Disease Burden by Illness - Disability Adjusted Life Years United States, Canada and Western Europe, year olds Unipolar depressive disorders Alcohol use disorders Schizophrenia Iron-deficiency anemia Bipolar affective disorder Hearing loss, adult onset HIV/AIDS Chronic OPD Osteoarthritis Road traffic accidents Source: WHO – World Health Report, 2001

5 1.“The mood-elevating effects of fluoxetine [Prozac] are not evident after initial exposure to the drug but require its continued use for several weeks. This delayed effect suggests that it is not the inhibition of serotonin transporters per se, but some adaptation to sustained increases in serotonin function that mediates the clinical actions of fluoxetine. However, where these adaptations occur in the brain, and the nature of the adaptations at the molecular level, have yet to be identified with certainty.” 2.“All current antipsychotic drugs exert their full therapeutic actions over weeks, suggesting that, like lithium and antidepressants, slowly developing adaptations (in this case to initial D2 dopamine receptor blockade) are required for their antipsychotic effects.” S. E. Hyman, E. Nestler, R. Malenka, 2008 Molecular Neuropharmacology : A Foundation for Clinical Neuroscience, 2nd Edition How do psychiatric drugs work? 4

6 Some psychiatric drugs, their targets, logP values, and half lives fluoxetine (Prozac) serotonin transporter logP 3.4, hr clozapine (Clozaril) 5-HT2A serotonin receptor, GPCR logP 3.2, 8-12 hr ketamine (“special K”) NMDA glutamate receptor logP 2.2, 3-5 hr chlorpromazine (Thorazine) dopamine D2 receptor, GPCR logP 5.2, hr nicotine acetylcholine receptor logP 1.2, hr recreational / abused / addictive antipschizophrenicantidepressant 5

7 6 Each “advance” in biology has been tried out on schizophrenia. Early 20 th century, German classification & Nazi genetics 1950’s American psychiatrists (including Bettelheim) reacted with “schizogenic mother” or “refrigerator mother” hypothesis 1950, Linus Pauling fractionated urine; 1968 “Orthomolecular Psychiatry” in Science 1955, chlorpromazine  dopamine theories 1970, glutamate theories 1995, growth factors, development, migration 2000, genetics & genomics 2003, interneuron diversity 2005, inflammation There is no satisfactory explanation yet. Schizophrenia Pathophysiology In general, modern theories of schizophrenia emphasize abnormal balance among neuronal circuits or pathways, rather than individual neurons that either (a) degenerate or (b) fire too much or too little

8 Clinical potency of “classical” or “typical” antipsychotic drugs correlates best with dopamine D2 receptor blocking dose (Nestler, 16-6) 7

9 Clinical potency of “classical” or “typical” antipsychotic drugs correlates with dopamine D2 receptor blocking dose but modern “atypical” antipsychotics also block other GPCRs (Nestler, 16-8) Haloperidol Clozapine Quetiapine Risperidone Olanzapine Sertindole Affinity D1 dopaminergic D2 &D3 dopaminergic Muscarinic cholinergic 5HT2A serotonergic α1 adrenergic α2 adrenergic H1 histaminergic Conventionals: 8 Terrible side effects: tardive dyskinesia (mesostriatal pathway) weight gain, agranulocytosis Atypicals:

10 Major Depression I.Symptoms: Depression is defined as the affective state of sadness that occurs in response to a variety of human situations such as loss of a loved one, failure to achieve goals, or disappointment in love. Major depression differs only in intensity and duration or quality of the emotional state. From Berton and Nestler, Nature Reviews Neuroscience, 7: 137, 2006 (“Anhedonia”)

11 II. Characteristics of Major Depression A.Untreated episodes of major depression usually last from months. B.Major depression is a recurring disorder, usually worsening with age if not treated. C.The reported incidence of depression is 3 times higher in women than in men.

12  Along with changes in mood, the symptoms of Major Depression include disruption of basic drives (eating and sleeping), as well as cognitive disturbances (ruminations, guilt, indecisiveness, persistent thoughts of suicide).  This constellation of symptoms suggest involvement of cortical structures, a number of limbic brain structures, including the hippocampus, amygdala, and mesolimbic dopamine neurons (“reward centers”), and also midbrain structures controlling appetite. Depression involves dysfunction of many brain areas

13 From Berton and Nestler, Nature Reviews Neuroscience, 7: 137, 2006 Brain Areas that Regulate Mood FC: Frontal cortex (esp. prefrontal and cingulate) - cognitive function, attention HP: Ventral Hippocampus - cognitive function, memory NAc: Nucleus Accumbens (ventral striatum) - reward and aversion Amy: Amygdala - mediates responses to emotional stimuli HYP: Hypothalamus regulates sleep, appetite, energy, sex VTA: Ventral Tegmental Area - Sends dopaminergic projections to other areas DR: Dorsal Raphe nuclei - send serotonergic input to other areas LC: Locus Coeruleus - sends noradrenergic input to other areas.

14 I.The most successful medicines for treatment of Major Depression in recent years have been the selective serotonin reuptake inhibitors (SSRI’s) II.SSRI’s include Prozac, Zoloft, Celexa, Paxil… These drugs inhibit the specific serotonin transporters that take up serotonin after it is released. Thus, the drugs are believed to increase serotonin levels in the brain. III.Depression also is accompanied by misregulation of other neurohormonal pathways, for example the ACTH (pituitary) /cortisol (adrenal gland) pathway. NE and DA systems may also be misregulated. IV.The SSRI’s are not effective for about half of cases of depression. Thus, we have much more to learn about the various causes of depression. SSRI’s

15 Serotonergic systems in the brain The midbrain Raphe nuclei from Feldman et al., Principles of Neuropsychopharmacology, Sinauer, 1997 Rostral System Caudal System

16 B6 and B7 are the Dorsal Raphe nuclei, which contain 5-HT neurons whose endings branch profusely and do not make “conventional” synapses. This fiber system is called the D- system. B5 and B8 are the Median Raphe nuclei, which contain 5-HT neurons whose endings form repeated, more conventional synapses. This fiber system is called the M system. Rostral System from Feldman et al., Principles of Neuropsychopharmacology, Sinauer, 1997 B9 is also called the supralemniscal nucleus (SLN).

17 Two Serotonergic Fiber Types in the Forebrain Demonstrated by Immunocytochemical Labeling D-System - small arrows M-System - large arrows Scale bar = 10 µm from Tork, Ann. N.Y. Acad. Sci., 1990

18 17 Bipolar Disease 1. Clinical description 2. Genetics 3. Possible causes 4. Heterozygote advantage? 5. Therapeutic approaches

19 18 Bipolar disorder affects 1-1.5% of the population in most modern societies. Like depression, bipolar disorder is a mood disorder. It was formerly termed manic-depressive disorder, because patients have one or more manic or nearly manic episodes, alternating with major depressive episodes. 1st episode often in mid-20’s. Bipolar disorder often leads to suicide. 1. Clinical description, based on DSM-IV.

20 19 From DSM-IV Summary description of a manic episode Manic Episode is defined by a distinct period during which there is an abnormally and persistently elevated, expansive, or irritable mood. This period of abnormal mood must last at least 1 week (or less if hospitalization is required). The mood disturbance must be accompanied by at least three additional symptoms from this list: -inflated self-esteem or grandiosity, -decreased need for sleep, -pressure of speech, -flight of ideas, -distractibility, -increased involvement in goal-directed activities or psychomotor agitation, and Excessive involvement in pleasurable activities with likelihood of painful consequences If the mood is irritable (rather than elevated or expansive), at least four of the above symptoms must be present.... The disturbance must be sufficiently severe to cause marked impairment in social or occupational functioning or to require hospitalization, or it is characterized by the presence of psychotic features.....

21 20 No single gene causes bipolar disorder. Data for concordance among twins in bipolar disorder: “narrow” definition “broad” definition monozygotic (n = 55) 79%97% monozygotic, reared apart (n = 12) 69% dizygotic (n = 52) 24%38% 2. Genetics

22 21 Each new advance in neuroscience has been tried out on bipolar disorder-- as for schizophrenia. There is no satisfactory explanation yet. As for schizophrenia, present theories invoke: circuit properties early developmental events rather than individual neurotransmitter systems. 3. Possible causes of bipolar disease

23 22 Touched With Fire : Manic Depressive Illness and the Artistic Temperament by Kay Redfield Jamison "This is meant to be an illustrative rather than a comprehensive list...Most of the writers, composers, and artists are American, British, European, Irish, or Russian; all are deceased... Many if not most of these writers, artists, and composers had other major problems as well, such as medical illnesses, alcoholism or drug addiction, or exceptionally difficult life circumstances. They are listed here as having suffered from a mood disorder because their mood symptoms predated their other conditions, because the nature and course of their mood and behavior symptoms were consistent with a diagnosis of an independently existing affective illness, and/or because their family histories of depression, manic-depressive illness, and suicide-- coupled with their own symptoms--were sufficiently strong to warrant their inclusion." 4. Heterozygote advantage? autobiography: An Unquiet Mind by Kay Redfield Jamison

24 23 from Jamison KEY: H= Asylum or psychiatric hospital; S= Suicide; SA = Suicide Attempt Writers Hans Christian Andersen, Honore de Balzac, James Barrie, William Faulkner (H), F. Scott Fitzgerald (H), Ernest Hemingway (H, S), Hermann Hesse (H, SA), Henrik Ibsen, Henry James, William James, Samuel Clemens (Mark Twain), Joseph Conrad (SA), Charles Dickens, Isak Dinesen (SA), Ralph Waldo Emerson, Herman Melville, Eugene O'Neill (H, SA), Mary Shelley, Robert Louis Stevenson, Leo Tolstoy, Tennessee Williams (H), Mary Wollstonecraft (SA), Virginia Woolf (H, S) Composers Hector Berlioz (SA), Anton Bruckner (H), George Frederic Handel, Gustav Holst, Charles Ives, Gustav Mahler, Modest Mussorgsky, Sergey Rachmaninoff, Giocchino Rossini, Robert Schumann (H, SA), Alexander Scriabin, Peter Tchaikovsky Nonclassical composers and musicians Irving Berlin (H), Noel Coward, Stephen Foster, Charles Mingus (H), Charles Parker (H, SA), Cole Porter (H) Poets William Blake, Robert Burns, George Gordon, Lord Byron, Samuel Taylor Coleridge, Hart Crane (S), Emily Dickinson, T.S. Eliot (H), Oliver Goldsmith, Gerard Manley Hopkins, Victor Hugo, Samuel Johnson, John Keats, Vachel Lindsay (S), James Russell Lowell, Robert Lowell (H), Edna St. Vincent Millay (H), Boris Pasternak (H), Sylvia Plath (H, S), Edgar Allan Poe (SA), Ezra Pound (H), Anne Sexton (H, S), Percy Bysshe Shelley (SA), Alfred, Lord Tennyson, Dylan Thomas, Walt Whitman Artists Richard Dadd (H), Thomas Eakins, Paul Gauguin (SA), Vincent van Gogh (H, S), Ernst Ludwig Kirchner (H, S), Edward Lear, Michelangelo, Edvard Meunch (H), Georgia O'Keeffe (H), George Romney, Dante Gabriel Rossetti (SA)

25 24 People with bipolar disorder are often fascinating in the early stages.

26 Vincent Van Gogh paintings; 1600 drawings; 700 letters Life history: born and raised in the Netherlands Paris Arles 1888 (1st episode; cut off his own ear) hospitalized Auvers-sur-Oise 3 months. Shot himself 7/27/

27 26 I should like to do portraits which will appear as revelations to people in a hundred years' time. -- Letter to his sister Wil, 3 June 1890 Early 1889 Dr. Gachet June 1890

28 27 July 1890

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31 30 Surgery to remove large portions of the brain (1950’s-60’s) Electroconvulsive shock therapy (ECT). Now administered under anesthesia. Various electrode placements, pulse widths, and frequencies “In situations where medication, psychotherapy, and the combination of these interventions prove ineffective, or work too slowly to relieve severe symptoms such as psychosis (e.g., hallucinations, delusional thinking) or suicidality, electroconvulsive therapy (ECT) may be considered. ECT is a highly effective treatment for severe depressive episodes.“ -- National Institute of Mental Health Over a hundred theories have been offered to account for the efficacy of ECT. 5. Therapeutic approaches to bipolar disorder Surgical and electrical intervention

32 31 Li + ion Therapeutic effects begin in ~ 5 d, require several wk. Li + is quite poisonous at higher doses. Valproic acid and other anticonvulsants These also require several wk for full effects. Therapeutic approaches to bipolar disorder Drugs (upper left-hand region of the periodic table)

33 32 1. We don’t know, but there are now some good guesses. 2.All ideas about Li + assume an intracellular target. Li + enters cells freely through several channels and ion-coupled transporters that normally serve for Na +. Intracellular concentrations of Li + are probably several mM. 3.Most ideas about Li + involve enzyme inhibition. Most of the suspected enzymes manipulate high-energy phosphate bonds. How does Li + act? Three exemplar patients in the early days of Li +

34 Contemporary ideas about psychiatric drugs have emphasized binding to the classical targets at synapses... “Inside-out” mechanisms emphasize binding to the same classical targets, but within the endoplasmic reticulum and cis-Golgi

35 BloodLungs H+H+ Like most drugs, nicotine is a weak base. Its neutral form passes through 6 plasma membranes in ~ 20 s logP = 1.1 = log (solubility in octanol / water) 34 CSF Alvelolar epithelium Brain capillary

36 35 Nucleus UPRE Plasma nAChR Nicotine in CSF Classical Pathway: Channel activation & desensitization → Do neurons survive Despite stressors? Unfolded protein response membrane COPII vesicle Sec 13/31 Sar1 Sec24 Sec23 ATF6 Golgi Pharmacological Chaperoning→ upregulation M3-M4 loop H+H+ + ER BiP PERK IRE1 Clathrin Secretory vesicle COPII Golgi complex COPI Early endosome COPI Lysosome Ca 2+ Na + “Inside-out” Drug Action by Nicotine at α4β2 nAChRs Endoplasmic reticulum nAChR ATF6 IRE1 XBP1 eIF2 α PERK ATF4

37 1.Agonist binding eventually favors stable, high-affinity states (a “chaperone”) 10 6 channels nicotine 20 sec Three possible results of nicotine-nAChR binding in the endoplasmic reticulum “closed” AC Highest affinity Free Energy Reaction Coordinate “activated” “desensitized” Bound states with increasing affinity unbound agonist ? 2. Nicotine binding at subunit interface favors assembled nAChRs (a “matchmaker”) 3. Nicotine may displace lynx, directing nAChRs toward cholesterol-poor domains (an “escort”) nicotine lynx 36

38 R. L. Wiseman, C. M. Haynes, D. Ron Cell 2010 The three arms of the ER stress / unfolded protein response pathway 37

39 38 During chronic exposure to nicotine, α4β2 nAChRs are selectively upregulated. Pharmacological chaperoning is necessary but not sufficient for upregulation. Other sequelae of chaperoning: changed stoichiometry, reduced ER stress and reduced UPR. Upregulation proceeds similarly in clonal cells, rodent brains, and smokers’ brains. Inside-out Pharmacology of Nicotine Effects at α4β2 nAChRs Now we’re assessing gene expression in identified neurons chronically exposed to nicotine. Inside-out pharmacology is a powerful concept for nearly all CNS drugs: They are all membrane-permeant weak bases.

40 The discovery criteria for psychiatric drugs lead to excellent intracellular chaperoning 1. High bioavailability implies high membrane permeation All psychiatric drugs have logP > 2 2. Good stability in the body implies simple or little enzymatic breakdown. Half-life is ~ 1 day. 3. Good selectivity, few off-target effects imply high-affinity binding to the target Kd < 1 μM, often ~ 10 nM a. “Chaperoning”: (i) Transporter ligands are organic substrates ions, or antagonists, They favor two major binding states, “inward” vs “outward”. (ii) GPCR ligands (see next slide): agonists antagonists allosteric modulators “inverse” agonists b. “Matchmaking”: (i) Neurotransmitter transporters must homodimerize before leaving the ER (ii) GPCRs homo- and heterodimerize, in some cases required for ER export, in some cases favored by ligands 39

41 Pharmacological chaperoning of GPCRs 40 receptormutant /WTdrug classreference adenosine A1mutantagonists; antagonists(Malaga-Dieguez et al., 2010)Malaga-Dieguez et al., 2010 dopamine D4both transported dopamine; quinpirole; antagonists (Van Craenenbroeck et al., 2005)Van Craenenbroeck et al., 2005 gonadotropin- releasing hormone mutantantagonists (Conn and Ulloa-Aguirre, 2011)Conn and Ulloa-Aguirre, 2011 histamine H2bothagonist, inverse agonist(Alewijnse et al., 2000)Alewijnse et al., 2000 opsinmutant--(Noorwez et al., 2008)Noorwez et al., 2008 δ-opioidmutantantagonist(Leskela et al., 2012)Leskela et al., 2012 μ-opioidmutantagonists, antagonists(Chaipatikul et al., 2003)Chaipatikul et al., 2003 melanin conc. hormone mutantantagonist(Fan et al., 2005)Fan et al., 2005 melanocortin-4bothantagonist, inverse agonist(Tao, 2010)Tao, 2010 vasopressin V1abothantagonist(Hawtin, 2006)Hawtin, 2006 vasopressin V1b/V3bothantagonist(Robert et al., 2005)Robert et al., 2005 vasopressin V2bothantagonists(Wuller et al., 2004)Wuller et al., 2004

42 Enzyme or channel Transcription factors Nucleus Intracellular messenger kinase cascade Drug + In CSF + Endoplasmicreticulum Golgi H+H+ ATF6, CREB- H IRE1 XBP1 p-eIF2 α PERK ATF4 Nucleus UPRE Drug + in CSF Transcription factors ATF6 + + Neutralpermeant drug   BiP PERK IRE1 + + H+H+ ER Golgi β- arrestin A.Inhibition of plasma membrane GPCR, and downstream effects B. Intracellular pharmacological chaperoning of GPCR, and downstream effects Most papers suggest... We suggest... Two mechanisms for gene activation downstream from antipsychotic drugs

43 “Nearly” cell-autonomous actions of SSRI antidepressant treatment Kellermann group 42

44 43 Other diagrams Samuels & Hen, Eur J. Neurosci, 2011 Adult Neurogenesis Inside-out actions would occur here

45 Gene activation is too brief to account for the “therapeutic lag” Axonal transport provides a natural delay in the “inside-out” mechanism. Speed: ~ 1 mm / day. Suggests that equivalent effects would require briefer delays in animals with shorter axons 44 Marks et al, 1985 Dendritically localized events Days of nicotine infusion Mouse hippocampus

46 45 How does acute ketamine produce antidepressant effects within 2 hr? Monteggia & Duman groups suggest... (1) involve BDNF synthesis & release, (2) occur in the dendrites, (3) require protein synthesis, (4) do not require gene activation. The effects NMDA Receptor kinases↓ BDNF secretion BDNF mRNA BDNF↑ Dendritic Golgi Outside-in Ca 2+ + Decreased Ca 2+ flux Dendritic ER COPII BDNF mRNA p-eIF2α↓ pPERK↓ Escorting BDNF secretion BDNF↑ Inside-out BiP PERK IRE1 H+H+ + ER NMDA Receptor We suggest...

47 “Acid trapping” of nicotine might 1.keep nAChRs desensitized until they are exocytosed; 2.serve as a reservoir for nicotine Cell nAChR membrane Clathrin Endoplasmic reticulum nAChR Secretory vesicle COPII Golgi complex COPI Early endosome COPI Lysosome pH nic + nic CSF Nicotine in CSF See detailed calculations for antipsychotics: Tischbirek et al, Neuron &

48 What knowledge do we need next? As usual, we need cell biology & biochemistry 1. Reconstituted, cell-free systems for ER exit and retrieval 2.Better real-time markers for compartmentalized receptors and transporters a. Imaging mass spectrometry b. Plasma membrane binding only? Possible with impermeant derivatives c. ER binding only? More challenging, especially for antagonists. 3.Better measurements of pathway-specific gene activation (RNA-Seq) 4.Analyze newly synthesized proteins 47

49 Contemporary ideas about psychiatric diseases have emphasized synaptic and signaling deficits... “Inside-out” mechanisms emphasize that ~30% of a cell’s proteins enter the ER, and additional nuclear and cytoplasmic proteins control their synthesis & trafficking.

50 49 Polygenic the disease occurs only if several genotypes are present together Genetically Multifactorial several distinct genes (or sets of genotypes) can independently cause the disease Partially penetrant nongenetic or epigenetic factors are required, or the disease is inherently stochastic Polygenic Genetically Multifactorial Partially Penetrant Three concepts used in describing complex diseases such a schizophrenia

51 50 Concordance for Lifetime Risk of Schizophrenia 0%10%20%30%40%50% general population 1st cousins uncles/aunts nephews/nieces grandchildren half siblings parents siblings children fraternal twins identical twins shared DNA 100% 50% (1st-degree relatives) 25% 12.5% Like Kandel Figure % 17% 1% (independent of culture) Genetics (David Helfgott’s father; John Nash’s son)

52 51 GABAergic “chandelier cell” in human cerebral cortex has many large axon terminals... DeFelipe, Brain (1999) 122, 1807 (Cajal Institute, Madrid) Pyramidal Cells Ch terminals ~ 100 μm Ch terminals Ch axon... and plentiful somatic ER Jones, J. Comp. Neurol., 1984

53 End of session 52


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