11/5/2009
Psychosis:
“Who can it be now?”
Timothy S. Allen, M.D.
Assistant Professor
Department of Psychiatry
University of Kentucky
Etiology
• Schizophrenia can be considered psychosis
•
•
•
•
in its purest form.
Usually develops in late teens/early 20
20’ss
Has prodromal stage in teens
Stress usually precipitates 1st break
Strong familial links
Hallucinations
Delusions
• Auditory are by far the most common
• Alcohol withdrawal
• Late dementia
• Severe Depression
• Severe Personality Disorder
• Visual>Tactile>Olfactory>Gustatory
• Jealousy
• Grandeur
• Conspiracy
• Somatic
• Capgras’ Syndrome
Disorganized Thought
Negative Symptoms
• Thought Blocking
• Poverty of Speech
• Loose Associations
• Echolalia
• Social Withdrawal
• Blunted Affect
• Poor Hygiene
• Odd Beliefs (e.g. ESP)
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Drugs/Meds That Cause Psychosis
Neurological Disorders
• Alcohol
• Amphetamines
• THC
• LSD, PCP, MDMA
• Inhalants
• Sedative/Hypnotics
• Cocaine
• Alzheimer’s
• Complex Partial Seizures (TLE)
• Huntington’s
Huntington s
• Hydrocephalus
• Lupus Cerebritis
• Parkinson’s
• Pick’s (fronto(fronto-temporal dementias)
Infectious Causes
Endocrine
• Brain abscess
• Hepatic Encephalopathy
• Mononucleosis
• Malaria
• Meningitis
• Syphillis
• Addison’s
• Cushing’s
• Hypo/hyperthyroidism
• Hypo/hyperparathyroidism
Others
Ask Yourself
• Heavy Metals
• Thiamine Deficiency (Korsakoff’s)
• Vitamin B12/Folate Deficiency
• Rx Steroids
• Neoplasms (almost anywhere)
• Are there cognitive deficits? (delirium)
• Episodic or continuous?
• Are there negative symptoms?
• Have there been prodromal symptoms?
• Have they had a mood disorder?
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Work--up New Psychosis
Work
Theories of Etiology
• Complete physical and neurological exam
• Mental Status Exam
Exam-- neuropsych testing
• Labs
Labs-- Chem7,
Chem7 Ca,
Ca CBC,
CBC thyroid,
thyroid LFT
LFT’ss,
• Dopamine Theory
• Serotonin Theory
• Glutamate (NMDA) Theory
• Theory of Relativity
•
•
•
VDRL, Vit B12/Folate, HIV
Tox Screen
CT or MRI
EEG
Dopamine Theory
Dopamine Pathways
• Discovery of
•
•
•
•
•
•
Chlorpromazine
Increased benefit of
pure D2 antagnoists
t
i t
like haloperidol
Psychotic reactions to
DA agonists
Nigrostriatal
Mesolimbic
Mesocortical
Tubuloinfundibular
Serotonin Theory
Serotonin Pathways
• Atypical Antipsychotics
Antipsychotics-- 5-HT2A blocking
• LSD is a hallucinogen
• Mostly from the
raphe nuclei
• More narrowly
di t ib t d than
distributed
th
NE, NMDA and
DA
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NMDA Theory
Treatment Implications
• Hyper
Hyper--excitability of
• Older drugs used D2 blocking as their only
•
positive symptoms of
psychosis
E t
Ecstacy
iis a
hallucinogen
•
•
antipsychotic activity ((Haldol
Haldol,, Thorazine
Thorazine))
They are very effective for positive
symptoms but much less so for negative
ones
Drug companies wanted to make more $
First Generation Antipsychotics
Atypicality
• Very good at minimizing positive
• Older antipsychotics were classed by their
•
•
•
•
•
symptoms
Little effect on Negative Symptoms
Extra--Pyramidal Side Effects (tremor,
Extra
cogwheel, bradykinesia)
bradykinesia)
Akathesia
Tardive Dyskinesia
Dyskinesia-- permanent
Enter The Second Generation
• All SGA’s also bind D2
• There are several profiles for binding D2
which may reflect efficacy and side effect
profiles
•
affinity to block the D2 receptor. Higher
binding meant higher efficacy.
Atypical (2nd gen) antipsychotics have
created a new paradigm.
D2 and 5HT2A remain important but
receptor affinity is not the only issue.
Binding
-1
D2
Clozapine
6.8
210
Haloperidol
17
2.6
Olanzapine
Quetiapine
Risperidone
Ziprasidone
H1
M
5HT2A
3.1
9
2.59
260
>10K
102
44
20
0 087
0.087
36
1 48
1.48
8.1
770
19
1400
31
2.7
3.77
5.2
34K
0.15
2.6
2.6
4.6
2440
0.12
Richelson E, Souder T Life Sciences 68 (2000) 29-39.
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Atypicality
Rates of Dissociation from the D2 Receptor
• Kapur et al suggest a fast dissociation
•
•
(koff) accounts for 99% of the variation
between antipsychotic’s Kd at D2.
A lower D2 affinity leads to a
“surmountable” blockade, allowing
displacement for natural dopamine surges.
Less EPS?
“Atypical” Antipsychotics
MEDIUM
FAST OFF
Quetiapine
Clozapine
Remoxipride
Amisulpride
p
Traditional Antipsychotics
SLOW
Haloperidol
Olanzapine
Sertindole
0 1 2
4
6
8 10
Raclopride
20
Chl
Chlorpromazine
i
30
Minutes for 50% release from cloned D2
Kapur S, Seeman P, Am J Psychiatry 158:3, 360-369
Seeman P. Can J Psychiatry 2002
Theories for Atypical Action:
Brief Occupation of D2 by
Quetiapine & Clozapine
Loose at D2
Little or
no EPS
Quetiapine
Typical
100
Haloperidol 7.5 mg/d (Nordstrom et
Qu
eti
ap
2
Cloza
pine
350
ine
5
Clozapine
al, 1992)
K at D2 receptor (n
nM)
% of D2 Recep
ptors Occupied
Atypical
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
mg/d
40
0m
g/d
10
15
20
24
Hours after oral dose
10
1
0.1
Olanzapine
Ziprasidone
Trifluoperazine
Risperidone
Chlorpromazine
Haloperidol
Doserelated
EPS
Dopamine K
Perphenazine
EPS
Adapted from:
Seeman P. Can J Psychiatry 2002
Seeman P. Can J Psychiatry 2002
Risperidone (Risperdal
Risperdal))
Theories for Atypical Action:
Inverse Agonism of 5HT-2A
K for 5HT-2A inverse a
agonism, nM
1000
Atypical
Typical
100
10
Quetipine
Haloperidol
Trifluoperazine
Thioridazine
Chlorpromazine
Fluphenazine
Olanzapine
Clozapine
Risperidone
1
0.1
Adapted from:
• The most “typical” of the atypicals
• Strong D2 and 5HT2A binding
• 24 hour D2 occupancy
• Most EPS
• Moderate Weight Gain
• Generic Available
• Depo form called Consta is q2 weeks
Seeman P. Can J Psychiatry 2002
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Olanzapine (Zyprexa
Zyprexa))
Quetiapine (Seroquel
Seroquel))
• Weaker D2 binding than risperidone
• 24 hour D2 occupancy
• Strongest H1 binding (Sedation and
• Weakest D2 affinity
• Longer D4 and 5HT2A binding than D2
• In a patient at steady state,
state 12 hours after
•
•
Weight gain?)
1/3 of people gain 1/3 body weight
a dose D2 occupancy is close to zero
5HT2A occupancy is related strongly to
plasma levels and remains at 70% or
better for 14 hours when dosed above
50mg
Kapur S, et al Arch Gen Psych 2000, 57, 553-559
Transient D2 Receptor Occupancy
58% D2
occupancy
400 mg
Quetiapine
3 hours
9 hours
Prolactin 19 mcg/mL
ELEVATED
64% D2
occupancy
450 mg
Quetiapine
2 hours
20% D2
occupancy
Prolactin 4 mcg/mL
NORMAL
0% D2
occupancy
24 hours
Prolactin 27 mcg/mL
ELEVATED
Prolactin 2 mcg/mL
BELOW NORMAL
Gefvert O, et al Psychopharmacology (1998) 135: 199-126
Kapur et al. 2000
Ziprasidone (Geodon)
Arapiprazole (Abilify
Abilify))
• Strong D2 and 5HT
5HT--2a
• No Weight Gain
• Low EPS
• QTc prolongation (~15 msec)
msec)
• BID dosing
• Needs highest dosing (80 BID+)
• A D2 partial Agonist
• In theory would allow enough D2
•
•
•
stimulation to prevent EPS
However, due to extremely strong D2
binding, has high EPS
No Weight Gain
No Prolactin Rise
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Clozapine (Clozaril
Clozaril))
CATIE
• Weakest at D2
• Clearly the most effective
• Works on D1,
D1 D4,
D4 and 5HT2A
• Agranulocytosis
Agranulocytosis=
= weekly monitoring
• Many S.E.
S.E.-- orthostasis
orthostasis,, sialorrhea
• Worst for weight gain, DM
• NIMH Trial comparing antipsychotics
• End point : time to discontinuation
• All SGA
SGA’ss and perphenazine (Trilafon
Trilafon)) were
To give or not to give
Other Uses of SGA’s
• Weight Gain
• Weight independent risk of DM2
• Hypertriglyceridemia
•  Prolactin
• Big Lawsuits
• Informed Consent
• Low incidence of Tardive Dyskinesia
• Bipolar Mania
• Severe Personality Disorder
• Refractory Depression
• Agitation of Dementia (vs. risk of stroke)
• Sleep
Sleep-- DO NOT DO THIS!!!!!!
• Autism
• Generalized Anxiety (after SSRI’s)
Personality Disorders
Robert Currie, III
• An enduring pattern of perceiving,
• On June 14, 1997 Robert Currie stabbed
•
relating, and thinking about the
environment and oneself that is seen in a
wide range of social and personal
situations.
Cluster BB- Antisocial, Borderline, Histrionic
and Narcissitic present most often
•
•
•
EQUAL
One exception was Zyprexa which was
statistically BETTER
his mother at least 6 times killing her. He
also attacked his friend Gene Battistelli,
slitting his throat.
Robert had a long history of psychiatric
hospitalizations and treatment
The insanity defense was raised.
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11/5/2009
French Quarter
Past Social History
• Robert’s parents divorced in 1985, when
•
•
Robert was 4 years old. He lived with his
mother until 1993.
He lived with his father from 1993 until he
ran away to New Orleans in April 1997.
He returned to Tennessee and moved in
with mother later that month.
The Nightlife
School
Psychiatric Diagnoses
• IQ tests revealed a full scale IQ of 111.
• He performed poorly in Junior High
6/2/93
Major Depression c Psychotic Features
Intermittent Explosive D/O
2/3/95
MDD c Suicidal and Psychotic Features
IED, S
IED
Substance
b t
Ab
Abuse
•
•
receiving mostly C’s
C s and D
D’ss
He had multiple suspensions for fighting,
smoking and being disruptive.
He threatened to burn down the school in
1993 that led to his first hospitalization.
Substance Abuse
Alcohol
3/98
MDD with Psychotic Features
Substance Abuse
LSD
“all the time” in school
since 12 yo
Daily at first, now
monthlyy
About 12x
Nitrous Oxide
“Drug of Choice”
Cocaine
IV 3-4x in New Orleans
Marijuana
3/29/95 Depression NOS
Borderline Personality D/O
PCP
Absinthe
Mushrooms and Heroine
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11/5/2009
Past Medical History
Delinquent Behavior
• Birth TraumaTrauma- forceps delivery and seven
• Robert ran away from father’s house in
•
•
•
•
days of right
right--sided paralysis
Fall from a chair at age one
Delayed speech development
Sexual abuse by a priest at age nine
April 1997, to New Orleans
He began using IV Cocaine and Heroine,
as well as …
The Motive?
• Jackie Currie goes to New Orleans and
•
•
LSD
En Route
• En route to New Orleans the trio stops for
•
lunch and Robert convinces Jackie to buy
him a 4 inch bladed hunting knife at a
pawn shop.
They arrive in New Orleans on June 13th,
1997
brings Robert back to live with her in
Bartlett, TN
J ki pays $3000 to enrollll Robert
Jackie
R b
in
i an 8
week Christian Camp in Minnesota, to
begin June 16th, 1997
Robert convinces Jackie to take him and
Gene Batistelli back to New Orleans prior
to the Camp
New Orleans
They check
into the
“Historic
French
Market
Inn”
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11/5/2009
French Market Inn
The Day Before
• 6/13 at 6:30pm Currie and Batistelli go to
Kaldi’s Coffee Shop and find ‘The Draven’
• Currie buys and takes 2 hits of …
That Morning
• Currie, Batistelli and The Draven meet up
with 4 other youths and stay out smoking
marijuana until 4:30 am.
• Robert takes one or two more hits of…
LSD
June 14th
• They return to the hotel to sleep around
5:00 am
• Batistelli is awakened by Currie and his
•
mother cursing at each other.
Batistelli tries to calm Currie down. Currie
says to him, “I hate you… You are out to
get me, it’s all part of the plan.”
LSD
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11/5/2009
June 14th
The Insult
• Currie, Batistelli and The Draven go to
• The boys return to
•
the hotel. Jackie says
to Robert,
“Remember
Remember the night
Jason got drunk at
the house. That’s the
way you are acting
right now.”
Kaldi’s around 8 am, but Currie is kicked
out
Currie says, “I wish I had a gun… to kill
myself… but then I wouldn’t die.”
The Crime…
Matricide
• Robert “snatches” the room keys from
• Jackie runs toward Robert begging for
•
•
Jackie and leaves, Batistelli follows him a
moment later
They meet in the hallway, Currie slashes
Batistelli’s throat with the knife his mother
had just bought him.
Matricide
•
Robert to calm down and give her the
knife
He begins stabbing her. She screams “No
Robert! Stop! No Robert!”
Batistelli throws an ashtray and begins to
hit Robert with a metal chair.
Robert Currie, III
• As Jackie Currie lay there bleeding to
•
•
death, Currie says, “This is how I end it
all,” and cut his own arms.
Robert goes up stairs and is eventually
found in room 205 in a yoga position.
He had cut both wrists and his throat.
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11/5/2009
The Weapon
Sanity at the Time?
Room 205
bathroom,
where Robert
was found.
Sanity at the Time?
McNaughten Standard
EMT: “Why did you do it?”
Robert: “The Draven made me do it.”
“Is
Is my mother dead?
dead?”
Police Officer: “Yes”.
Robert: “ I can’t believe I killed my mother.”
Louisiana Statute RS 14:14
If the circumstances indicate that because
of a mental disease or mental defect the
offender was incapable of distinguishing
between right and wrong with reference
to the conduct in question, the offender
shall be exempt from criminal
responsibility.
Questions
• Was Currie psychotic at the time of the
murder?
• Is he schizophrenic?
• How did drugs impact his behavior?
• Was he criminally responsible?
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