How do psychiatric drugs work?

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 1

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.

2

Disease Burden by Illness - Disability Adjusted Life Years

United States, Canada and Western Europe, 2000

15-44 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

2

2

6

6

Percent of Total 8

8

Source: WHO – World Health Report, 2001

How do psychiatric drugs work?

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, 2n

d Edition 4

Some psychiatric drugs, their targets, logP values, and half lives antipschizophrenic antidepressant recreational / abused / addictive nicotine acetylcholine receptor logP 1.2, 0.5 -2 hr chlorpromazine (Thorazine) dopamine D2 receptor, GPCR logP 5.2, 16-30 hr ketamine (“special K”) NMDA glutamate receptor logP 2.2, 3-5 hr clozapine (Clozaril) 5-HT2A serotonin receptor, GPCR logP 3.2, 8-12 hr fluoxetine (Prozac) serotonin transporter logP 3.4, 24-72 hr 5

Schizophrenia Pathophysiology

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.

Population of US Public Mental Insitutions 600 500 400 300 200 100 0 1800 1850 1900 1950 2000 2050 year 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 6

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

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

Terrible side effects:

Conventionals: tardive dyskinesia (mesostriatal pathway) Atypicals: weight gain, agranulocytosis 8

I.

Major Depression

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.

(“Anhedonia”) From Berton and Nestler, Nature Reviews Neuroscience, 7: 137, 2006

II. Characteristics of Major Depression A.

Untreated episodes of major depression usually last from 7 - 14 months.

B.

C.

Major depression is a age if not treated.

women than in men. recurring disorder , usually worsening with The reported incidence of depression is 3 times higher in

Depression involves dysfunction of many brain areas

 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.

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.

From Berton and Nestler, Nature Reviews Neuroscience, 7: 137, 2006

SSRI’s

I.

II.

III.

IV.

The most successful medicines for treatment of Major Depression in recent years have been the ( SSRI’s ) selective serotonin reuptake inhibitors 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.

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. 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.

Serotonergic systems in the brain

Rostral System Caudal System The midbrain Raphe nuclei from Feldman et al., Principles of Neuropsychopharmacology, Sinauer, 1997

Rostral System

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.

B9 is also called the supralemniscal nucleus (SLN).

from Feldman et al., Principles of Neuropsychopharmacology, Sinauer, 1997

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

Bipolar Disease 1. Clinical description 2. Genetics 3. Possible causes 4. Heterozygote advantage?

5. Therapeutic approaches 17

1. Clinical description, based on DSM-IV.

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.

18

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 . . . . .

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2. Genetics No single gene causes bipolar disorder.

Data for concordance among twins in bipolar disorder: “narrow” definition “broad” definition monozygotic (n = 55) monozygotic, reared apart (n = 12) dizygotic (n = 52) 79% 69% 24% 97% 38% 20

3. Possible causes of bipolar disease 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.

21

4. Heterozygote advantage?

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."

autobiography:

An Unquiet Mind

by Kay Redfield Jamison 22

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) 23

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

24

1886 Vincent Van Gogh 1853-1890 750 paintings; 1600 drawings; 700 letters Life history: born and raised in the Netherlands Paris 1886-88 Arles 1888 (1st episode; cut off his own ear) hospitalized 1888-1890 Auvers-sur-Oise 3 months. Shot himself 7/27/1890 1887 1887-88 25

Early 1889

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 Dr. Gachet June 1890 26

July 1890

27

28

29

5. Therapeutic approaches to bipolar disorder Surgical and electrical intervention 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.

http://www.acnp.org/G4/GN401000108/CH106.html

30

Therapeutic approaches to bipolar disorder Drugs 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.

(upper left-hand region of the periodic table) 31

Three exemplar patients in the early days of Li + How does Li + act?

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.

32

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

Lungs

Like most drugs, nicotine is a weak base.

Its neutral form passes through 6 plasma membranes in ~ 20 s

Alvelolar epithelium Brain capillary Blood CSF H +

logP = 1.1 = log (solubility in octanol / water)

34

“Inside-out” Drug Action by Nicotine at α4β2 nAChRs

Na +

Classical Pathway: Channel activation & desensitization

Ca 2+ Clathrin nAChR Plasma membrane Early endosome Secretory vesicle Golgi COPI Nicotine in CSF ATF6 Lysosome Golgi complex COPI COPII vesicle

Sec 13/31 Pharmacological Chaperoning→ upregulation ATF6

COPII Endoplasmic reticulum

Sec24 Sec23 Sar1 IRE1

nAChR

Unfolded protein response → Do neurons survive Despite stressors?

XBP1

UPRE

PERK ATF4 eIF2 α

Nucleus M3-M4 loop H + ER

+

IRE1 BiP PERK 35

Three possible results of nicotine-nAChR binding in the endoplasmic reticulum 1. Agonist binding eventually favors stable, high-affinity states (a “chaperone”) unbound agonist Bound states with increasing affinity 10 6 channels “closed” nicotine 20 sec “desensitized” Reaction Coordinate Highest affinity 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

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

Cell

2010 37

Inside-out Pharmacology of Nicotine Effects at α4β2 nAChRs During chronic exposure to nicotine, α4β2 nAChRs are selectively upregulated.

Now we’re assessing gene expression in identified neurons chronically exposed to nicotine.

Pharmacological chaperoning is necessary but not sufficient for upregulation.

Upregulation proceeds similarly in clonal cells, rodent brains, and smokers’ brains.

Other sequelae of chaperoning: changed stoichiometry, reduced ER stress and reduced UPR.

Inside-out pharmacology is a powerful concept for nearly all CNS drugs: They are all membrane-permeant weak bases.

38

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

Pharmacological chaperoning of GPCRs

receptor

adenosine A1 dopamine D4 gonadotropin releasing hormone histamine H2

mutant /WT

mutant both mutant both opsin δ-opioid μ-opioid melanin conc. hormone melanocortin-4 vasopressin V1a vasopressin V1b/V3 vasopressin V2 mutant mutant mutant mutant both both both both

drug class

agonists; antagonists transported dopamine; quinpirole; antagonists antagonists agonist, inverse agonist - antagonist agonists, antagonists antagonist antagonist, inverse agonist antagonist antagonist antagonists

reference

( Malaga-Dieguez et al., 2010 ) ( Van Craenenbroeck et al., 2005 ) ( Conn and Ulloa-Aguirre, 2011 ) ( Alewijnse et al., 2000 ) ( Noorwez et al., 2008 ( Leskela et al., 2012 ) ( Fan et al., 2005 ( Tao, 2010 ) ( Hawtin, 2006 ) ) ( Robert et al., 2005 ) ( Wuller et al., 2004 ) ) ( Chaipatikul et al., 2003 ) 40

Two mechanisms for gene activation downstream from antipsychotic drugs Most papers suggest . . .

A.

Inhibition of plasma membrane GPCR , and downstream effects Drug

+

In CSF

+

β arrestin

+

a Intracellular messenger bg Enzyme or channel kinase cascade Transcription factors Nucleus We suggest . . .

B. Intracellular pharmacological chaperoning of GPCR, and downstream effects Golgi

+

ATF6 Drug

+

in CSF Golgi Neutral permeant drug H +

XBP1 ATF6, CREB H

Endoplasmic reticulum

+ + IRE1

Transcription factors

UPRE PERK ATF4 + + p-eIF2 α

Nucleus H + IRE1

+ +

BiP PERK ER

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

Adult Neurogenesis

Inside-out actions would occur here Other diagrams Samuels & Hen,

Eur J. Neurosci, 2011

43

Gene activation is too brief to account for the “therapeutic lag” Mouse hippocampus Marks et al, 1985 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 Days of nicotine infusion Dendritically localized events 44

How does acute ketamine produce antidepressant effects within 2 hr?

The effects (1) involve BDNF synthesis & release, (2) occur in the dendrites, (3) require protein synthesis, (4) do not require gene activation.

Monteggia & Duman groups suggest . . .

We suggest . . .

Outside-in NMDA Receptor Inside-out Ca 2+ BDNF secretion BDNF secretion Decreased Ca 2+ flux Dendritic Golgi Dendritic ER BDNF ↑ BDNF mRNA

kinases

↓

Escorting + + + pPERK

↓

+

COPII

+

BDNF ↑

p-eIF2 α

↓ BDNF mRNA NMDA Receptor

+

H + IRE1 BiP PERK ER 45

“Acid trapping” of nicotine might 1. keep nAChRs desensitized until they are exocytosed; Early endosome 2. serve as a reservoir for nicotine Clathrin nAChR Cell membrane COPI Secretory vesicle Lysosome Nicotine in CSF COPI nAChR pH nic

+

nic CSF 5.2 100 6.0 30 Golgi complex 6.3 20 6.5 10 COPII Endoplasmic reticulum 6.7 3 7.2 1 & 7.2 1 See detailed calculations for antipsychotics: Tischbirek et al,

Neuron

2012

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

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.

Three concepts used in describing complex diseases such a schizophrenia 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 Genetically Multifactorial Polygenic Partially Penetrant 49

Genetics (David Helfgott’s father; John Nash’s son) shared DNA

Concordance for Lifetime Risk of Schizophrenia

100% 50% (1st-degree relatives) 25% 12.5% identical twins fraternal twins children siblings parents half siblings grandchildren nephews/nieces uncles/aunts 1st cousins general population 17% 1% (independent of culture) 0% 10% 20% 30% 40% 48% 50% Like Kandel Figure 60-3 50

Ch terminals Ch axon

GABAergic “chandelier cell” in human cerebral cortex has many large axon terminals . . .

. . . and plentiful somatic ER

Pyramidal Cells

~ 100 μm DeFelipe,

Brain

(1999) 122, 1807 (Cajal Institute, Madrid) Jones,

J. Comp. Neurol.

, 1984 51

End of session 52