Transcript Sari-bill schiz slides 01 - University of Illinois Archives

Schizophrenia
Professor Sari Gilman Aronson
Professor William Greenough
Medical Behavioral Sciences
A Few Historical Tidbits
1952
Chlorpromazine noted to ameliorate psychosis
late 1950s Widespread clinical use of chlorpromazine
1967
Haloperidol released in the United States
1975
CT scan technology in clinical use (EMI scan)
1985
MRI scan technology in clinical use
1990s
“Atypical” antipsychotics released
PSYCHOACTIVE DRUGS
Drugs have revolutionized psychiatric treatment since the 1950's.
Most psychoactive drugs act stereospecifically on receptors, enzymes, or
other active protein elements of the nerve cell (e.g., ion channnels,
blocked by local anesthetics).
Existence of a drug can lead to discovery of a mechanism (e.g., opiates,
salicylates, chlorpromazine).
The majority of psychoactive drugs affect synaptic transmission.
Drugs can have synergystic (combinatorial) interactions with other drugs.
(Some may be good, many are bad)
Many drugs have side effects (We will talk about tardive dyskinesia, a
side effect of long term treatment with antipsychotic drugs).
1. The Natural History of Schizophrenia
•Generally an insidious onset.
•Possible history of complications during pregnancy and birth.
•History in early adolescence of excessive shyness, social
awkwardness, withdrawal from social relationships, inability to form
friendships, sometimes academic difficulties.
•Onset of acute psychosis in late adolescence or early adulthood.
Symptoms may be brief or vague. Infrequent onset after age 40.
•Variable course among patients. Episodes of acute psychosis
superimposed on baseline functioning. Baseline function may show
residual symptoms or patient may be in remission.
.
2. The Natural History of Schizophrenia
• Good prognosis associated with:
 acute onset
 past high functioning and excellent interpersonal adjustment
 good response to antipsychotic medications
 absence of negative symptoms
 absence of a secondary affective disorder (depression or
mania)
• In a sample of 200 patients followed after 30 years of disease
 20% asymptomatic
 25% moderate symptoms
 55% severe symptoms
Clinical Presentation
•
POSITIVE SYMPTOMS: represent a distortion or exaggeration of a
normal function and include delusions, hallucinations and
abnormalities of language and behavior.
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SYMPTOM
Hallucinations
Delusions
Formal Thought Disorder
Behavioral Disorganization
FUNCTION DISTORTED
Perception
Inferential Thinking
Language
Behavioral Control
Clinical Presentation
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NEGATIVE SYMPTOMS: represent a diminution or loss of function
including poverty of speech and content of speech (alogia),
affective blunting, asociality, anhedonia, and avolition.
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SYMPTOM
Alogia
Affective Blunting
Avolition-Asociality
Anhedonia
Attentional Impairment
FUNCTION LOST
Fluency of speech
Emotional Expression
Volition and drive
Hedonic capacity
Attention
Diagnosis of Schizophrenia (1)
DSM-IV Diagnostic Criteria (Abbreviated)
• Characteristic symptoms: Two or more of the following, each
present for a significant portion of the time during a 1 month
period (or less if successfully treated):
– delusions
– hallucinations
– disorganized speech (e.g. frequent derailment or
incoherence)
– grossly disorganized or catatonic behavior
– negative symptoms, i.e., affective flattening, alogia, or
avolition
• Social/occupational dysfunction: For a significant portion of the
time since the onset of the disturbance, one or more major areas
of functioning such as work, interpersonal relations, or self-care
are markedly below the level achieved prior to the onset (or when
the onset is in childhood or adolescence, failure to achieve
expected level of interpersonal, academic, or occupational
achievement).
Diagnosis of Schizophrenia (2)
DSM-IV Diagnostic Criteria (Abbreviated)
• Continuous signs of the disturbance for at least 6 months.
This 6 month period must include at least 1 month of
symptoms (or less if successfully treated) that meet
Criterion A, and may include prodromal or residual
symptoms (Criterion A symptoms manifested in attenuated
form or negative symptoms present).
• Symptoms not due to Schizoaffective Disorder or a Mood
Disorder.
• Symptoms not due to a general medical condition.
Subtypes of Schizophrenia (1)
•
Paranoid Type
 preoccupation with one or more delusions or frequent auditory hallucinations
 no disorganized speech, disorganized or catatonic behavior, or flat or inappropriate
affect
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Disorganized Type
 Prominent disorganized speech, disorganized behavior, flat or inappropriate
behavior
 does not meet criteria for Catatonic Type
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•
Catatonic Type
clinical picture dominated by at least 2 of the following:
 motoric immobility as evidenced by catalepsy (body remains in one position) or
stupor
 excessive motor activity that is apparently purposeless and not influenced by
external stimuli
 extreme negativism (apparently motiveless resistance to all instructions or
maintenance of rigid posture against attempts to be moved) or mutism
 peculiarities of voluntary movement as evidenced by posturing (voluntary
assumption of inappropriate or bizarre postures), stereotyped movements,
prominent mannerisms, or prominent grimacing
 echolalia or echopraxia
Subtypes of Schizophrenia (2)
•
•
Undifferentiated Type
Symptoms are met for Criterion A, but criteria are not met for Paranoid,
Disorganized or Catatonic Types
•
Residual Type
 Absence of prominent delusions, hallucinations, disorganized
speech and grossly disorganized or catatonic behavior
 Continuing evidence of disturbance as indicated by presence of
negative symptoms or 2 or more Criterion A symptoms present in
an attenuated form (odd beliefs, unusual perceptual experiences).
Case
Daniel is an 18 year old white middle class male brought to the hospital emergency room by his
parents. His parents were concerned that Daniel had been acting strangely lately, although Daniel
denied any problem saying, "I've seen the light."
Daniel lives with his parents and is a sophomore at a local college. He has always been a good
student, but his grades fell significantly one month ago. He has always been a rather quiet child, but
seemed to socialize well with other children until about age 12. At that time, he began to withdraw
from friends and family, choosing to spend alot of time alone in his room. He enjoyed reading and
playing guitar. He told the examiner that he liked to read fantasy novels and that he thought highly of
John Lennon. His parents said that Daniel never dated and in fact seemed intimidated by girls.
Daniel stated, "females are the right hand of the devil" but he would not elaborate on that thought.
His parents began to feel more concern 8 months ago during the first semester of his freshman year
in college as he seemed even more withdrawn from them than usual. He also began talking about
John Lennon more frequently, telling his parents that John "knew the way" and that he needed to
"find his meaning in this meaningless world". Within the past two months, Daniel seemed even more
preoccupied with concerns of life and death and has stopped going to class. His parents became
alarmed when he told them this morning that he believes that he can communicate with John
Lennon by getting John’s “karma in my mind”. In addition, he told them that “I am becoming the
walrus…I can use my tusks to read the waters of life.” Daniel has not slept or eaten for the past two
days. Daniel and his parents stated that he had never used drugs or alcohol.
Daniel is the eldest of 3 children with siblings age 15 and 11. He has never been seriously ill and has
no history of head injury, seizures, fever, or toxic exposure. His development as an infant and young
child was unremarkable except for the problems noted previously. His family denies a family history
of psychiatric disorder, but remembered a maternal cousin who was unusual and spent much of his
later life living alone. There was a family story about how this man used to collect thousands of
magazines and lock himself in his house for months.
Mental Status Evaluation
The Mental Status Evaluation (MSE) is an assessment of a patient’s appearance, behavior, speech,
mood, affect, thought content, thought process, orientation, memory and other cognitive
functioning, judgement and insight at one point in time. A MSE can change quickly if the patient’s
functioning is fluctuating, such as when a patient is delirious. The MSE will be covered in detail in
the second year psychiatry course. Daniel’s MSE is presented to clarify his symptoms.
Daniel was dressed in tattered blue jeans, a V-neck sweater without a shirt and loafers without
socks. He was unshaven and looked tired although he remained alert throughout the interview. He
did not want to sit down in a chair but preferred to stand near the door, often turning his head
towards it when there was some noise in the hallway. He was distant and made poor eye contact
with the examiner. Daniel looked at his watch or at a book about John Lennon which he had
brought with him. His speech was somewhat slowed and quiet. He seemed mildly agitated,
standing still then pacing for a few minutes. Daniel did not want to describe his mood. His affect
was blunted and he expressed little emotion. He denied depression and suicidal thoughts. Daniel
was reluctant to discuss his thoughts. He did talk about his interest in Lennon's life as a "guide"
for him, but denied thinking about dying or joining John. On one occasion, he said that he was
worried that he might be killed by someone who "fought the principles of God and Lennon". Daniel
had thought blocking on several occasions and had loose associations. Daniel was very guarded
and suspicious and seemed to be attending to internal stimuli. At one point during the interview,
he mumbled something softly but would not discuss it with the examiner. He was alert and
oriented with no fluctuations in consciousness. His attention was poor as a result of his
preoccupation with himself. He knew the names of 6 past presidents, was familiar with current
events, and did not seem to be impaired intellectually. Daniel did not want to perform any tests of
memory saying, "that's stupid- there is nothing wrong with my memory". He had little insight into
his problem and showed poor judgement, i.e. "it really doesn't matter if I eat as God will provide
sustenance for me".
Questions And Discussion Points
•What psychiatric problem is Daniel experiencing?
•. Schizophrenia, probably paranoid
•. Key Diagnostic Features of Schizophrenia
–At least 2 psychotic features present for at least a month
». Hallucinations
». Delusions
». Disorganized speech: incoherence, frequent derailment
». Grossly disorganized or catatonic behavior
». Negative symptoms: affective blunting, anhedonia, lack of motivation
–Impairment in social or occupational functioning or self-care
–Duration for at least 6 months with 1 month of active symptoms (unless treated)
–Symptoms not due to a mood disorder or schizoaffective disorder
–Symptoms not due to a medical, neurological or substance use disorder
»(Schizoaffective disorder usually diagnosed when manic or depressive symptoms are
prominent and consistent part of patient’s long term psychotic illness)
•. Diagnostic Subtypes of Schizophrenia
–The diagnosis of schizophrenia also contains the related issue of subtypes of schizophrenia. The
purpose of defining subtypes is to improve predictive validity and subsequent treatment. Subtypes
identified in DSM- IV include:
». Catatonic: motor abnormalities such as rigidity and posturing
». Disorganized: disorganized speech and behavior, flat affect
». Paranoid: paranoid symptoms in the absence of catatonic or disorganized features
». Undifferentiated: some combination of the above
List the symptoms that Daniel is
experiencing
• delusions
• probable hallucinations
• social withdrawal
• decreased sleep and appetite
• impairment in functioning in school
• agitation
• blunted affect
• thought blocking
• loose associations
• little insight and poor judgement
Treatment
Daniel was offered hospitalization which he initially refused, but
decided to accept after some discussion. He said, “I’ll come in to be
sure that no one shoot me like they did John…he warned me that
something bad might happen.” His medical work-up showed a healthy
18 year old male. He was started on haloperidol 5 mg at bedtime and
discharged in 5 days to his parents home. He was seen weekly by a
psychiatrist in the outpatient clinic. Within 5 days of starting
medication, he was sleeping better and gaining weight. After 2 weeks,
he seemed calmer, but still talked about his connection to John
Lennon. His haloperidol was held at this dose for 2 more weeks as
research has shown that low dose treatment takes longer to work, but
is easier for patients to tolerate. Within a month, he no longer seemed
to be hallucinating and was more interactive. His delusions had
“softened” and he seemed less fearful of being hurt. After 4 months of
treatment, Daniel stated, “I don’t think about John Lennon much
anymore. He is still important to me, but my mind took off on its own”.
He was much improved, but still was socially withdrawn and had a
blunted affect.
Theories on the Mechanism(s) of
Schizophrenia
What brain abnormalities might underlie such a potentially
devastating disorder? Daniel’s case was relatively mild.
Genetic Vulnerability: MZ (identical) twin concordance >4
X more likely than DZ (sibling) twins; MZ twins average
50% discordance rate suggesting environmental influences
Experience-based Vulnerability: More frequent in lower
socioeconomic classes; stress may precipitate relapse; social
network an important buffering influence (often disrupted
by schizophrenic’s own behavior)
Brain structure-based theories implicate
frontal and medial temporal lobes
* Ventricular enlargement: In effect this means that tissue
adjacent to the ventricles shrinks--temporal lobe,
hippocampus
*Several reports of shrinkage of frontal lobes, fewer
synapses per neuron, reduced dendritic field size in
prefrontal brain regions
*fMRI and PET (blood flow/metabolism) studies indicate
“hypofrontality,” decreased activity of frontal lobes
Pharmacological treatment-based theories
*From Chlorpromazine in the 1950s to the recent past,
“typical” neuroleptic drugs, effective in schizophrenia had
in common the blockage of the D2 Dopamine receptor.
(They differ in therapeutic and negative side effects.)
* The Dopamine systems of the brainstem project to
limbic (“mesolimbic”) and frontal cortical
(“mesocortical”) brain regions. Both may be involved in
Schizophrenia.
*The Serotonin system projects to all regions of the
brain from its origin in the raphe nuclei of the brainstem.
*We won’t detail receptor actions because there will
probably be more receptors when you’re MDs.
What do these drugs do? They largely
act at synapses.
Can we discern, from their effects at
synapses, what the basis of
schizophrenia might be?
There are Two Classes of Neurotransmitter Receptors:
Ionotropic Receptors, when activated by
neurotransmitter, allow ions to cross the cell membrane
via channels
Metabotropic Receptors, when activated by
neurotransmitter, trigger enzymatic activity
The same neurotransmitter, e.g., glutamate or serotonin,
can activate both ionotropic and metabotropic receptors
Ionotropic receptors will be used for illustration of the
way drugs work.
This might be a metabotropic
synapse, in which case the
neurotransmitter would drive
enzymatic changes in the
Post-synaptic cell
“Atypical” Antipsychotic Drugs: Affect both Dopamine
and (especially) Serotonin Systems
* These drugs appear to do better at controlling both
positive and negative symptoms of schizophrenia
* Some “atypicals” (e.g. clozapine) have high affinity for
newly discovered D4 Dopamine receptors
* Atypicals appear Not to cause Tardive Dyskinesia
Drug Therapy for Schizophrenia:
Medication alone is never the treatment for a patient
Medications may be important components of a larger
overall treatment plan
What are some of the side effects of
antipsychotics?
• Imbalance of dopaminergic (nigrostriatal) and cholinergic
systems leading to extrapyramidal side effects (acute
dystonic reaction; parkinsonian side effects such as tremor,
rigidity, and bradykinesia; akathisia).
• Nigrostriatal dopamine receptor supersensitivity leading to
tardive dyskinesia.
• Anticholinergic side effects such as dry mouth, sedation,
difficulty with urination, blurry vision, orthostatic
hypotension.
• Weight gain.
• Elevation of prolactin leading to sexual dysfunction,
altered/lowered mood, loss of menses in female patients,
inability to become pregnant, weight gain.
What are some of the problems that patients face when
deciding to take medication?
• Lack of acceptance of mental disorders as diseases- the perception that mental illness is
willful and psychologically driven.
• Inability to face the illness or a desire to run away and pretend that the illness will go
away on its own.
• Lack of support from important others like family or mate.
• Realistic problems like job loss and social rejection.
• General fear of mind-altering medications (which may be quite irrational as the
individual may not fear the use of alcohol, cigarettes, marijuana, or cocaine).
• The disease itself leads to fear of treatment (e.g. paranoid hallucinations telling the
patient to not trust anyone or that the medication is really poison).
• Unhappiness with side effects of medication.
• Fear of tardive dyskinesia.
• Discomfort with the physician or other members of the treatment team.
How can these problems be minimized?
• Education of the patient about his/her disease; the probable
course and risks if untreated, and the probable course and
benefits/risks if medication is used.
• Develop an understanding of the patient’s point of view about
his/her disease, symptoms, hopes for the future, fears.
• Identify the patient’s strengths and help the patient mobilize all
his/her individual and social resources. Involve the family when
this is helpful.
• Acknowledge the possible risks of medication treatment and
assure the patient that he/she will be followed carefully.
• Encourage open communication between patient and physician.
How is tardive dyskinesia treated?
• Discontinue the antipsychotic and hope for the best. The
patient may become ill again.
• Initiate clonidine (a presynaptic alpha agonist that leads to
down-regulation of the DA receptors and hypotension).
• Initiate reserpine (depletes monoamines and may cause
depression).
• Obtain tetrabenazine from Canada (depletes monoamines
with lower risk of depression).
MRI sheds new light on schizophrenia (Early onset Schizophrenia)
- Schizophrenia, one of the most debilitating of mental illnesses, is also one of the most mysterious. Though treatment
can control the illness in more than half of patients, little is known about what actually causes the disorder -- which
affects about one in every 100 persons worldwide -- and how it affects the mind. UCLA researchers may have just
unraveled part of the mystery. Using magnetic resonance imaging, or MRI, and a new analysis technique, they have
created the first images showing the toll the disease takes on the brain. The results are reported in the Proceedings of the
National Academy of Sciences . Throughout the five-year study, the researchers performed brain scans every two years
on a group of 34 teenagers. The study population was made up of clinically diagnosed schizophrenics taking
antipsychotic medications, another group of patients taking the same medications for mood disorders, and normal teens.
The schizophrenic patients were diagnosed with the illness before adolescence, an unusual group that represents about 5
percent of all schizophrenic patients. The images that resulted from the study "stunned" the scientists, according to lead
researcher Paul Thompson. Rather than small, gradual changes, Thompson and his colleagues noted a dramatic wave of
destruction of the gray matter in brain tissue of schizophrenic patients. Thompson described the wave as moving across
the brain "like a forest fire." While the healthy teens lost an average of 1 percent of gray matter per year, the
schizophrenic patients lost up to 5 percent a year, with loss greatest among individuals with the most severe symptoms.
Study Important, But No Direct Therapy Yet Additionally, the movement of tissue loss across the brain seemed to be in
sync with the appearance of disease symptoms that would originate in those parts of the brain. Starting off in the brain's
logic center, the parietal cortex, tissue loss continued at a dramatic rate into the auditory part of the brain and then onto
motor areas. Thompson says this sequence corresponds with the typical course of the disease. The first signs include
confused or illogical thinking. As the illness progresses, more bizarre symptoms such as psychosis (unusual
perceptions) and hallucinations occur. "The study represents another step forward in our understanding of
schizophrenia," says Dr. Steve Lamberti, associate professor of psychiatry at the University of Rochester Medical
Center. Lamberti says the strength of the study is the detail on the nature of deterioration and progression of the illness
in young people, and the evidence that brain changes were not related to antipsychotic medications but to the disease
process itself. Though experts acknowledge the importance of the study's findings, they say it is limited for now.
"Though there is no direct therapy application at this point ... there is a window of hope here." says Dr. Robert
Freedman, Chairman of the Department of Psychiatry and the University of Colorado Health Sciences College. "Most
of us thought the damage was done in utero," says Freedman, but "the study suggests the changes can possibly be
observed during adolescence." Freedman calls the study groundbreaking as it has "opened up a window to a very
complicated piece of biology that none of us completely understand." Yet, he says, "A lot of work still has to be done."
END