Better Than Prozac

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Better Than Prozac

• Creating The Next Generation of Psychiatric Drugs
• Samuel Barondes

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How many of you know someone who takes a
psychiatric drug ?

• Tens of millions of Americans take psychiatric
  drugs, many more than one and every day.

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Main Points A Big Picture

• All current psychiatric drugs are effective
  remedies for some people with mental disorders.
• None are fully effective, and all have
  undesirable side effects.
• Not rational come from chance discoveries.
• But understandableall influence brain signaling.
  
• To make fundamental improvements need deeper
  understanding of disorders the promise of
  genetics and brain biology.

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What is a Mental Disorder? DSM-IV

• A clinically significant behavioral or
  psychological syndrome or pattern associated with
  present distress or disabilitymust not be a
  culturally sanctioned response to a particular
  event (death of a loved one) neither deviant
  behavior (e.g.,political,religious, or sexual)
  nor conflicts between the individual and society
  are mental disorders unless the deviance or
  conflict is a symptom of a dysfunction..(Line
  with normal real, blurry)

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Criteria for DisorderMDD, GAD.

• Major Depressionmarkedly depressed mood for 2
  weeks, wt change, sleep change, fatigue,
  worthlessness, inability to think, suicidal ideas
  etc.
• Generalized Anxiety Disorder excessive worry for
  at least 6 months, difficult to control, sleep
  disturbance, irritability, mind going blank etc.
• Often have both. Not sharp diagnoses.

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Consequences of Blurriness

• May overprescribe
• May underprescribe
• May misprescribe
• Like all doctors, psychiatrists must be aware of
  these pitfalls.
• So caution, trial and error, not just come back
  and see me in 3 months.

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Huge Problem

• 26 of Americans 18 have diagnosable mental
  disorder in a given year
• Major Depressive Disorder 6.7 Dysthymic
  disorder 1.5 Bipolar 2.6
• Schizophrenia 1.1
• Anxiety Disorders 18.1 (Panic, OCD, PTSD,GAD,
  Social Phobia)
• ADHD 4.1 (18)
• Many meet criteria for 1 (e.g., MDD GAD)
• ---NIMH
  website

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The First Blockbuster

• 1940s, antihistamine that is also sedating
• 1949, used off-label in anesthesia
• 1950, derivative,more sedating
• 1951-2, tested it for mania (bipolar), psychosis
  (schizophrenia etc.) not just sedating gradual
  relief of delusions
• 1955,widespread use (chlorpromazine, Largactil,
  Thorazine)

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A Second Blockbuster

• Search for me too drugs
• Antihistamine that looks like chlorpromazine
• But this drug was not antipsychotic
• Gave it to patients with severe depression. It
  worked!
• Marketed in 1957 as imipramine (Tofranil). Led to
  Prozac (1987)
• 1960sit also works for anxiety disorders!

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HOW THEY WORK INFLUENCE NEUROTRANSMITTERS
Chlorpromazine Receptor Dopamine
Imipramine Reuptake Transport Serotonin,
Norepinephrine
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SERT
Same process with Norepinephrine NORT
A Serotonin Receptor
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Complexities

• Trillions of connections (synapses) each with
  multiple receptors
• 14 serotonin receptors, 5 dopamine receptors,
  each with different distribution, functions
• Each drug affects many, in different ways
• Adaptation (weeks of delay) changing effects
• Amazing any drug has coherent favorable effect

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Other Surprising Findings

• 1937 amphetamine, decongestant, Rx to improve
  school performance (later,ADHD)
• 1949, lithium, salt substitute, Rx for mania
• 1959, potential antibiotic,Rx for anxiety
  (Librium--first benzodiazepine, then Valium)

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By 1960

• All main classes antipsychotics,
  antidepressants, mood-stabilizers, stimulants,
  minor tranquilizers
• Each influences action of neurotransmitters
  mainly dopamine, serotonin, norepinephrine, GABA
• Next decades alternatives with better efficacy
  and/or side effects, not fundamental difference

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Some Recent Modifications

• Chlorpromazine Atypicals such as Risperdal,
  Geodon, Seroquel, Zyprexa, Abilify
• Imipramine SSRIs such as Prozac,
  Zoloft,Paxil,Luvox, Celexa, Lexapro
• Imipramine SNRIS such as Desipramine, Strattera
• Imipramine dual action drugs such as Effexor,
  Cymbalta

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How Effective Are Drugs for Major Depression?

• Measured with scales (HAM-D) e.g.7normal,
  30very depressed (54 max.)
• Significant relief-- 50-60 have symptoms down by
  at least half (than placebo.
• But even with drug, only about 33 get
  remission--free of symptoms (7 or so)

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STARD (Sequenced Treatment Alternatives to
Relieve Depression)

• 4,041 patients with MDD
• Drug (SSRI) plus 3 switches or adds
• 33, 25,16,6 remission
• Overall 70 remission of those who completed, but
  some quit.
• Lessons switch and add can help, CBT can help,
  but many still dont remit.

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So Where Do We Go From Here? Genes.

• Need to learn more about what makes certain
  people vulnerable.
• Genes and environment.
• Genes once seemed hopelessly mysterious, so
  emphasized environment.
• Now genes are getting easier to study.
• May be many different genetic forms of
  depression, may be reason for different response.

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Why Turn to Genetics? Risk to First Degree
Relatives

• Schizophrenia 10X
• Bipolar Disorder 10X
• Major Depression (Early Onset) 5X
• ADHD 5X
• OCD 5X
• Panic Disorder 5X
• --- NIMH Genetics Workgroup (1999)

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Human Genes and Variants

• 30,000 human genes (each encodes a protein with
  complex actions) 2 copies
• There are variants of each gene (tiny changes may
  alter functions)
• Small number of common variants
• We are learning a lot about human genome and
  common variants

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Example of Alzheimers

• Why do small fraction of people get it before age
  50, many more start getting it after 60--some
  earlier, others later, still others OK after 90?
• Different gene variants increase risk of early
  form (genes that influence A-beta) and late form
  (APOE4) identifying them is helping design
  medicines.

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Genetics of Later Onset Alzheimers

• APOE gene (cholesterol,heart disease)
• 3 variants APOE2, APOE3, APOE4,all common
• One APOE4 increases risk of Alzheimers
• Two APOE4, bigger increase (50 by age 70)
• Knowing about APOE4 can be used for diagnosis,
  has not yet led to treatment.
• Other genes also important. Interactions.
• Environment also important. Boxers APOE4

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Genetics of Depression

• Search for genes very active
• But difficulties because of importance of
  environmental factors, and because so many
  different gene variants appear to be involved,
  complex interactions.
• Difficulties illustrated by SERT gene--which
  makes the protein that is a target of Prozac

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Variants of Serotonin Transporter Gene
Makes less SERT
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Variants of SERT Gene, Life Stress and Major
Depression ---Caspi et al, Science,
301, 386, 2003
Short variant increases risk. But life stress
(age 20-26) also important.
GxE interaction is big challenge to gene
discovery.
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Prospects Via Genetics

• Whole genome association and sequencing-keeps
  getting cheaper (1000 genome)
• Will find many susceptibility genes (recent
  success with diabetes)
• Identification of biological steps in causation
  (genetics and other leads)
• Creation of drugs that block critical steps
• But, as in other branches of medicine, it wont
  be easy

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Conclusion

• We have lots of useful drugs and know enough
  about them to improve them.
• Most people can be helped with what we have--but
  only with thoughtful care.
• But we must do better we must keep searching for
  drugs that are better than Prozac.

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Some New Leads

• Substance P antagonists. Developed for pain, but
  now evidence that they may relieve depression,
  anxiety.
• CRF antagonists for depression, anxiety
• Rolipram. Found to be an antidepressant. Then
  shown to inhibit PDE4. Now PDE inhibitors are
  being explored (influence 2nd messengers)

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Potential Refinements

• Search for non-sedating and non-addicting
  benzodiazepines via targeting specific alpha
  subunits of GABA-A receptors
• Pharmacogenetics to sort out responders and
  non-responders (e.g. SSRIs) or those with
  vulnerability to side effects (e.g.antipsychotics)

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Alzheimers in Transgenic Mice

• Insertion of pathogenic human variant
  (transgene) mouse Alzheimers
• APP variant from patient Alzheimers symptoms by
  12 months (middle age)
• APP variant PS1 variant Alzheimers symptoms
  by 6 mos (more A-beta)
• Use these mice to test inhibitors of beta or
  gamma secretase as treatments

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Examples of Gene Variants

• Depression SERT(along with stressors), CREB-1
  (females only)
• Schizophrenia Neuregulin-1,Dysbindin
• None immediately suggest a new drug

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Why Turn to Genetics? 5.Two Big Problems

• Heterogeneity--different gene variants can
  increase risk of same disorder
• Polygenic disorders--combinations of gene
  variants
• Example of both--Alzheimers disease

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Example Alzheimers Disease

• Original case 46 y.o. F with paranoia,
  depression, poor memory
• Died age 51, brain had amyloid plaques
• Reported 1906, German psychiatric soc.
• Named by Kraepelin in 1910 for Alois Alzheimer
• Early onset,
• Later onset, common, many gene variants
  environment

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Genes as Tools

• Once a gene variant is found to play a role in a
  disorder, it can be used in many ways to help
  figure out how the altered protein function
  influences the biological processes that lead to
  symptoms.
• This makes possible design of treatments that
  block a critical step in the complex causal
  process (e.g. secretase inhibitors could decrease
  A-beta)

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Search for Genes for Other Mental Disorders

• A major effort is underway to find the gene
  variants that make certain people more vulnerable
  to other mental disorders such as depression,
  bipolar disorder, anxiety disorders,ADHD,schizophr
  enia.Some have been tentatively identified.

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Happy Pills or Medicines?

• Is the goal to find cures for mental disorders
  or make people feel better?
• Penicillin is a cure, aspirin makes people feel
  better
• Psychiatric drugs we now use all have elements of
  both
• Variable effects on different people and in
  different states (example alcohol)

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Genetics of Early Onset Alzheimers

• 50 risk if one parent has it
• First known variant APP gene (encodes the
  protein that is cleaved to make A-beta, the
  peptide in amyloid)
• Also variants of previously unknown presenilin
  genes PS1, PS2
• Each variant increases A-beta in brain
• ? Rx block enzymes that make A-beta, antibodies
  that block A-beta.

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Extending the Use of Imipramine

• 1958, Donald Klein and Max Fink gave imipramine
  for at least 3 weeks to 200 inpatients
  ---irrespective of diagnosis
• 14 of the patients had an unanticipated response
  reduction of episodic anxiety and panic
• Conclusion imipramine is not only useful for
  depression but also for anxiety disorders (so too
  are successors)

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Pathogenesis and Cause

• Aspirin treats P, penicillin treats C
• Current antidepressants treat P
• Other potential targets of P (CRF system and
  steroids steroids and neuronal cell death)
• Can now interfere with P in new ways irrespective
  of C--in addition to aspirin (and ibuprofen) have
  new drugs that interfere with steps in
  inflammation.

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Why Turn to Genetics? Other Evidence

• Familial doesnt prove heredity
• So need final proof find gene variants (and it
  is now possible to do this)

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Why Turn To Genetics? Implications

• Gene variants can be used for diagnosis
• Gene variants can lead to specific drugs
  (understanding complex functions)
• But must sort through 30,000 different human genes

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Causes of Depression

• Not simple cause like bacterial pneumonia
  (antibiotics kill bacteria)
• Risk factors e.g. recent loss
• Predisposition gene variants
• May be different kinds based on differences in
  both psychological and biological mechanisms.
• Differences reflected in variable response