Before we start:

1
Before we start

• Kroeger Prize Applications
• Due April 19, 2002
• Applications outside room 414
• Appendix pages for seminar on Web under Study
  Interactions and Study Questions

2
Drugs for Schizophreniaand Depression

• By Vahn Lewis

3
General Concept for Neurologic Disorders
4
Psychiatric Diagnosis

• Schizophrenia 1
• Depression
• 20 women,10 men
• Variants
• monopolar
• bipolar
• mania
• 25 of patients with schizophrenia have
  depression
• See Diagnostic and Statistical Manual 4 of the
  American Psychiatric Soc.DSMIV

5
Dental Branch Patient Case History

• Patient Alice B
• Health Compromises
• Schizophrenia and depression
• Smokes 2 packs of cig/day
• Hospitalized 6 mo ago to start new drugs
• Medical history
• Clozaril (clozapine) 200mg tid
• Zoloft (sertraline) 50mg am
• Desipramine 100 mg qd am
• Patient no longer taking following (per MDs
  order) chlorpromazine, benzotropine mysolate,
  and imipramine.

6
Development of Drugs For Psychiatric Disorders
7
Dental Issues in the Treatment of Psychiatric
Disease

• Xerostomia
• increased dry mouth due to drugs and disease
• increased caries
• increased tooth loss
• increased difficulty with dentures
• increased candida albicans
• Decreased ability to perform dental maintenance
• increased drug use in all populations
• (including elderly and children)
• may require increased recall visits
• may require assistance for maintaining oral
  health
• oral dyskinesias
• fluoride treatments helpful

8
Symptoms of Schizophrenia

• Diagnostic criterion 2 or more of the
  following, for more than a month
• "Positive" symptoms
• Delusions
• Hallucinations
• Disorganized speech
• Grossly disorganized or catatonic behavior
• "Negative symptoms
• i.e. affective flattening, alogia or avolition,
  etc.
• (Classifications DSMIV)

9
John Nash, Nobel Prize 1994,Schizophrenic
1960-1990

• Nash a solitary and introverted very bright
  child.
• He loved mathematics but other students teased
  him.
• Nash developed schizophrenic symptoms in about
  1960

• (I) started to see crypto-communists everywhere
  ... I started to think I was a man of great
  religious importance, and to hear voices all the
  time. I began to hear something like telephone
  calls in my head, from people opposed to my
  ideas. The delirium was like a dream from which I
  seemed never to awake.

10
Signs of Schizophrenia

• 1. Abnormal function of dopamine tracts in brain
• 2. Brain structure changes
• 3. Brain-function test changes
• 4. Genetic findings
• 5. Perinatal brain damage

Alan Chovil Schizophrenic Web site maintainer
11
Dopamine hypothesis of antipsychotic action

• Efficacy of antipsychotics correlates to binding
  to dopamine 2 (D2) receptors.
• recent interest in 5HT2
• recently-EAA hypothesis
• recently-GABA hypothesis
• several others...

12
Therapeutic Target for Antipsychotic Drugs

• Block dopamine receptors
• (at meso-limbic dopamine cells)
• Blocking acetylcholine receptors reduces
  extrapyramidal side effects (striatal)
• Blocking 5HT2 receptors reduces extrapyramidal
  side effects (cortical or basal ganglia)

13
Dopamine Receptors

• Dopamine Receptors
• D1 likeD1, D5 (? cAMP)
• D2 Like D2,D3,D4 (?cAMP)
• D2 -highly correlated to clinical effect.
• therapeutic and side effects
• D2 short isoform less EPS
• D4 enriched in heart and mesolimbic brain
  structures
• D3 enriched in mesolimbic and cortex and may have
  better side effect profiles

14
Side effects from blocking dopamine

• Striatal (Basal ganglia)-
• extrapyramidal effects (similar to Parkinsons
  disease)
• tardive dyskinesia- a serious movement disorder
  that presents after the medication is removed.
• Tubro-infundibular dopamine path
• gynacomastia or lactation in females or males.
• Block dopamine at chemoreceptor trigger zone
  (antiemetic)

15
Side effects from blocking other receptors
16
Antipsychotic Agents-Structural Classification

• Phenothiazines -Example-Chlorpromazine
• Thioxanthines-Thiothixene
• Butyrophenones- Haloperidol
• Diphenylbutylpiperidines-Pimozide
• Indoles - Molindone
• Benzamides-sulpiride (europe)
• Dibenzoxazepine-Loxapine
• Dibenzodiazepines- Clozapine

17
(No Transcript)
18
Uses for antipsychotic drugs

• Management of psychotic disorders
• Antiemetics
• Various other indications
• PCP psychosis, bipolar, disorder, migraine,
  Tourettes syndrome, Huntingtons chorea, Systemic
  Lupus Erythematosus,
• Dementia

19
Phenothiazines-1

• Early Antipsychotic
• Phenothiazines act at many receptors
• Antidopinergic (D1-D2)
• Anti-Serotoninergic (5HT2, etc)
• Antimuscarinic M1 (muscarinic)
• Coexistence of Anti DA and Anit-ACh activity
  reduces Parkinson's like side effects
• Antihistaminergic H1
• Antiadrenergic (alpha block) a 1- 2
• epinephrine reversal
• orthostatic hypotention
• HERG K channel block-prolonged QT syndrome

20
Phenothiazines-Example

• Chlorpromazine relative binding
  a1gt5HT2gtD2gtD1ltMlt?2 Older agents reduce delusions
  and hallucination i.e. "positive criterion"
• Is also antimucarinic xerostomia

21
Haloperidol-a butryophenone

• Selective Antipsychotic
• Haloperidol blocks D2 receptors preferentially
• Relative binding D2gtgta1gtgt5HT2gtD1
• Little anticholinergic action , high incidence
  of EPS
• Therefore antichoinergic agents added to therapy
  if EPSs are problematic.

22
Review-Side Effects of Classical Antipsychotic
Medication I

• Drowsiness -decreased motivation and emotion
• Parkinson's like side effects (syn-extrapyramidal
  side effects EPS)
• Due to action on the extrapyramidal dopamine
  system
• Supplementation with anticholinergic often
  necessary
• Dyskinesias -Abnormal movements
• Perioral tremor, rabbit syndrome
• Tardive dyskinesia (oral)
• Develops after antipsychotic discontinued

23
Side Effects of Classical Antipsychotic
Medication II

• Dry Mouth (antimuscarinic agents), constipation,
  glucoma
• Orthostatic hypotension (alpha blockade)-epinephri
  ne reversal
• Endocrine changes
• DA acts to block prolactin secretion
• gynecomastia on prolonged use
• Neruoleptic Malignant Syndrome
• Other --photosensitivity, weight gain,
  pigmentation, etc.

24
Atypical Antipsychotics AAP, Clozapine
(Clozaril)

• Blocks many receptors
• Mgt 5HT6,7,2H1 a1a 2 D4gt
• D1D2
• Low ExtraPyramindal Side effects (EPS)
• Improves positive and "negative" signs
• May improve course of disease
• Strong antimuscarinic action
• Paradoxically increases salivation
• Potential for hepatic, cardiovascular toxicity
  and agranulocytosis

25
Other AAPs -beyond the Dopamine hypothesis

• Examples
• Olanzapine (Zyprexa) --blocks 5HT2gtM1gta1D2 gtH1
  gtD1
• Resperidone (Risperdal) --blocks
• 5HT2AgtD2 a1a2 ltltltM
• Quetiapine (Seroquel)
• a1 gtH1gtD25HT2gtD1
• Sertindol (Serlect)
• 5HT2gt Alpha1D2gt D1
• Zisprasidone (Zeldox)
• 5HT2Alt5HT1A(agonist),5HT1D, lt5HT2Clt a1H1

Differences from traditional agents Low Extra
Pyramidal Side effects Improve positive
and negative" symptoms Low tardive
dyskinesias Less toxic than clozapine
26
(No Transcript)
27
Dental Branch Patient Case History

• Patient Alice B
• Health Compromises
• Schizophrenia and depression
• Smokes 2 packs of cig/day
• Hospitalized 6 mo. ago to start new drugs
• Medical history
• ClozarilÒ (clozapine) 200mg tid
• ZoloftÒ (sertraline) 50mg am
• Desipramine 100 mg qd am
• Patient no longer taking (per MDs order)
• chlorpromazine, benzotropine mysolate, and
  imipramine.

28
Patient Summary

• Patient was taking chlorpromazine and
  benzotropine. Benzotropine is a centrally acting
  anticholinergic drug. This combination of drugs
  suggests this patient was having trouble with
  extrapyramidal side effects.
• These drugs were replaced with clozapine an AAP
  with less EPS effect and more effect on negative
  symptoms (note patient is also being treated for
  depression) Clozapine can have serious side
  effects. She could have or develop (next slide)

29
Case Review II

• Possible hepatic damage, cardiovascular
  difficulties, or blood dyscrasias.
• We could anticipate that she will show
  orthostatic hypotension and epinephrine reversal.
• We should expect sedation and an increased
  sedative effect with any other CNS depressants.

Paradoxically, patients taking clozapine do not
report as much dry mouth as would be anticipated
from the drug receptor profile.
30
Case Continued

• Later, we might see that her clozapine changed to
  respiridone or one of the newer AAPs that are
  less toxic than clozapine.

31
Neuroleptic malignant syndrome (NMS) Symptoms

• 1. hyperpyrexia
• 2. muscle rigidity
• 3. altered mental status (including catatonic
  signs)
• 4. evidence of autonomic instability (irregular
  pulse or blood pressure)
• 5. elevated CPK
• 6. myoglobinuria (rhabdomyolysis)
• 7. acute renal failure
• 8. tachycardia
• 9. diaphoresis
• 10. cardiac arrhythmias

32
Neuroleptic Malignant Syndrome

• The management of NMS should include
• (1) Immediate discontinuation of antipsychotic
  drugs, amoxapine and other drugs not essential to
  concurrent therapy,
• (2) intensive symptomatic treatment and medical
  monitoring, and
• (3) treatment of any concomitant serious medical
  problems for which specific treatments are
  available

33
Signs of Schizophrenia 1. Dopamine disorder

• Dopamine tracts in brain
• 1. Meso-limbic - emotional regulation-possibly
  overactive in schizophrenia
• 2. Nigral-striatal - movement regulation
• Parkinson's disease-decreased
• Torette's Syndrome
• Minimal brain dysfunction
• 3. Tubro-infundibular - hormone regulation,
  example prolactin
• 4. Medullary-periventricular - ?eating
• 5. Incertiohypothalamic - ??

34
Signs of Schizophrenia 2. Brain structure changes

• Loss of cortical gray matter
• Loss of cells near cerebral ventricles (on MRI)
• Decreased frontal cortex function (PET)-increased
  white matter
• Decreased superior temporal gyrus size
• Decreased size and shape changes in amygdala and
  hippocampus of schizophrenia patients
• Decreases in thalamus size
• Increases in basal ganglia size

35
Signs of Schizophrenia 3. Function test changes

• Decreased frontal cortex blood flow during
  Wisconsin Card Sorting Test (PET Scan)
• Errors in slow visual pursuit, differences in
  slow startle accommodation
• Early childhood problems with motor skills and
  coordination

36
Signs of Schizophrenia 4. Genetic findings

• "Latent trait" (not simple mendelian
  transmission), pleiotrophy(single genes cause
  multiple manifestations),
• Several genetic loci on chromosomes 6,
  3,5,8,9,20,22
• Incidence of schizophrenia when both parents
  schizophrenic 46 one parent schizophrenic 18
  general population incidence 1

37
Signs of Schizophrenia 5. Perinatal damage

• Possible in utero fetal developmental
  abnormality for the schizophrenic patients
• influenza
• poor maternal nutrition
• In utero challenge-low O2
• Apparent errors in brain synaptic connections and
  pruning