Download schizophrenia

Louis Wain, 20th century
animal illustrator
◦ Background, stats, etc
◦ Biological Theories
 genetics
 CNS
 NT
◦ Pharmacological Treatments
◦ Current Issues




Incidence – 1% worldwide
◦ more than 2.2 million Americans.
Total financial cost of schizophrenia in US is
estimated at up to $65 billion a year.
1 in 3 patients who start an antipsychotic will
either switch medications or discontinue their
medication within a year.
56% of patients in a survey admitted to extended
periods of time when they are off medication and
32% of those patients cited side effects of their
medication as the primary reason.

Gender and Age differences
Copyright © Allyn & Bacon 2007

Gender and Age differences

increased mortality rate

increased risk of substance abuse

seasonal effect

seasonal effect

genetics
Epigenetics
How lifestyles and environment can change the way our genes are expressed

How are symptoms characterized?
◦ Positive Symptoms

Psychosis compromise syndrome of variety of
possible combinations
◦ can include bizarre thought disorders,
hallucinations, delusions, often accompanied by
disorganized speech and behavior

Other conditions that have psychosis as key
symptom
◦
◦
◦
◦
◦
substance-induced psychosis
psychotic disorders affiliated with medical condition
schizoaffective or schizophreniform disorders
mania, major depression, cognitive disorders, AD
to name a few…..

Negative symptoms◦ absence of response; flattened affect, anhedonia,
social withdrawal




positive and negative symptoms
aggressive/hostile symptoms
depressive/anxious symptoms
cognitive symptoms

cognitive deficits
◦ impediment to reintegration to society
◦ http://www.matrics.ucla.edu/
Copyright © Allyn & Bacon 2007

PET scans
◦ rCBF – regional cerebral blood flow
◦ 2DG- 2 deoxyglucose
◦ other radio isotopes
 radiotagged DA

brains are smaller

CT scans of patients with schizophrenia lateral and 3rd ventricles

reduced volumes of cortical gray matter

limbic system; found reductions in amygdala, hippocampus,

prefrontal cortex - functional deficits and anatomical deficits
found

thalamus - some studies show volume shrinkage or neuronal
loss

basal ganglia and cerebellum -
◦ progressive or static changes - data unclear

1950’s – introduction of phenothiazines
◦ chlorpromazine first- antihistamine
 one of the least expensive for treating psychosis

importance of the discovery



Blocking DA receptors
Resulted in the DA theory for schizophrenia
D2 receptor affinity clearly linked to
reduction in positive symptoms




l-dopa
amphetamine and cocaine
reserpine
alpha-methyl-para-tyrosine –
◦ blocks synthesis of DA, NE

apomorphine ◦ stimulates DA autoreceptor


classified based on chemical structure
phenothiazines and butyrophenones
Generic
acetophenazine
amisulpiride
chlorpromazine
chlorproxthixene
flupentixol
fluphenazine
fluspirilene
haloperiodol
loxapine
mesoridazine
molindone
perphenazine
pimozide
piperacetazine
prochlorperazine
thioridazine
thiothixene
trifluroperazine
trifluoropromazine
Trade name
Tindal
Solian
Thorazine, Largactil
Taractan
Fluanxol
Prolixin, Permitil
Imap, Redeptin
Haldol
Loxitane
Serentil
Moban, Lidone
Trilafon
Orap
Quide
Compazine
Mellaril
Navane
Stelazine
Vesprin



most antipsychotics – oral
parenteral
long-acting depot forms ◦ haloperidol decanoate (1/2 life 21 days)
◦ fluphenazine (14 days)

at least 11 traditional antipsychotic drugs are
available for injection

Numerous other uses for chlorpromazine
◦ nausea and vomiting, hiccups, to relieve severe
itching, manage psychotic component in acute
mania, to treat alcohol hallucinosis




refractory major depression
anorexia
Huntingtons disease
Personality disorders

differentiating drugs based on their potency
◦ specifically affinity for D2 receptors

useful for positive symptoms – not for
negative or cognitive deficits



100 mg of chlorpromazine ~ same results as 2 mg
haloperidol
◦ haloperidol – high potency antipsychotic
◦ chlorpromazine – low potency antipsychotic
low potency - more autonomic side effects (ie anti
ACh, anti adrenergic)
high potency - more motor side effects – called
extrapyramidal syndrome (EPS)


All antipsychotic drugs have common
mechanism of action
PET studies
◦ effective dose - drugs occupy 70 – 80% of available
D2;
◦ much higher – significant adverse side effects; EPS


- reports of 60 – 90% of patients receiving
antipsychotic medication develop
extrapyramidal symptoms
up to 50% readmissions are due to these side
effects
Extrapyramidal Motor Side Effects

Medication induced parkinsonism ~ 15-20%
◦ characteristics: rigidity, tremor, akinesia (lack of
movement), and bradykinesia (slowness of movement);
lead pipe rigidity, cogwheel rigidity, rabbit syndrome
 treatment – anticholinergic drugs

dystonia – spastic contraction of discrete muscle
groups
◦ occurs in 10% patients initiating therapy
◦ occurs most commonly in neck, eyes and torso
◦ reactions are sudden onset, dramatic in appearance, and
cause great distress (laryngospasm)
◦ txt: anticholinergics or antihistaminergics




hyperkinetic abnormal involuntary
movement disorder caused by sustained
exposure to antipsychotic medication
most commonly affects oral facial region
may arise after exposure to any med but
clozapine
occurs at a rate of ~ 4% per year

akathisia◦ characterized by somatic restlessness
◦ 20 – 25%
◦ complain of an inner sensation of restlessness and
an irresistible urge to move various parts of body
(often seen as pacing and inability to sit still)
◦ frequent cause of noncompliance
◦ less responsive to treatment than parkinsonism or
dystonia
◦ txt: anticholinergics, BZ also sometimes used






hypotension
dry mouth
constipation
urinary hesitancy or
retention
blurred near vision
dry eyes





narrow-angle
glaucoma
photophobia
nasal congestion
confusion and
decreased memory
sweating


most anti ACh symptoms decrease in 1 – 4
weeks but don’t completely remit
certain meds can reduce peripheral effects
but not central


traditional neuroleptics used less with the
advent of the newer atypicals
important difference is price


second-generation (atypical) antipsychotic
drugs, with $7·5 billion sales in the USA in
2003
atypicals - amisulpride, aripiprazole,
clozapine, olanzapine, quetiapine,
risperidone, sertindole, ziprasidone, and
zotepine)


history –
first atypical clozapine- 1990
◦ effective in proportion of patients that were
unresponsive to previous medication
◦ reduced negative symptoms
◦ reduced tardive dyskinesias
◦ maybe reduces cognitive deficits


much lower occupancy of D2 receptors (3040%);
multiple actions on monoamine receptors in
brain
◦ antagonist at both DA2 and 5HT 2A receptors.
CLOZARIL interferes with the binding of DA D1,
D2, D3 and D5 receptors, with a high affinity for
D4 receptor
 It does not induce catalepsy nor inhibit
apomorphine-induced stereotypy.
 This evidence, consistent with the view that
CLOZARIL is preferentially more active at limbic
than at striatal dopamine receptors, may explain
the relative freedom of CLOZARIL from EPS.
 CLOZARIL also acts as an antagonist at
adrenergic, ACh, histaminergic and
5HT receptors.

◦ risky side effects – agranulocytosis ~ 1%
 leukopenia -






clozapine – Clozaril – 1989 – generic 1998
risperidone – Risperdal - 1994
olanzapine – Zyprexa – 1996**
quetiapine – Seroquel - 1999
ziprasidone – Geodon aripiprazole (Abilify)- approved 11/2002**
◦ ~339 for 30 pills

** - currently class action lawsuits -


less D2 receptor blockade than traditional
AND also antagonize other DA receptors and
5HT2 receptors.
most (with the exception of clozapine) still
can produce EPS and a variety of other side
effects



Background:
◦ blockade of more than 65% of D2 receptors key
to antipsychotic efficacy
◦ occupation of 72% or more associated with
elevations in PRL
◦ occupation of 78% or more associated with EPS
and akathisia
so – some balance – optimal therapeutic
window?
common characteristic of atypicals is the
higher ratio of 5HT2 receptor blockade to
D2 than conventional




conventional antipsychotics and novel
demonstrate comparable affinity for 5HT2
receptor but lower affinity for D2
atypicals have a faster rate of dissociation
(unbinding) from D2 receptor
rank ordering (clozapine, quetiapine dissociate
faster followed by olanzapine, risperidone,
haloperidol and chlorpromazine respectively)
the faster the rate of drug dissociation, the
lower the rate of the treatment-emergent side
effects

metabolic syndrome –
◦ atypical antipsychotics have been associated with a
“metabolic syndrome” – insulin resistance,
hypertension, high serum lipids, obesity and
coagulation abnormalities,
◦ higher rates of diabetes
◦ *** olanzapine may produce this more than other
atypicals

Sedation- most common single side effect of
antipsychotic medication
◦ often most pronounced early in treatment
 strategies:

anticholinergic and antiadrenergic effects
◦ can occur in 10 – 50% of treated patients
◦ anticholinergic PNS effects occur via cranial nerves
and autonomic ns

increased seizure susceptability
◦ can be both 1st and 2nd generation although not
all neuroleptics are the same and much of the
data may be case reports

Endocrine effects:
◦ all standard antipsychotics increase PRL
secretion◦ galactorrhea – secretion of liquid from nipples (1
– 5% patients)
◦ oligomenorrhea – menstrual changes (up to 20%
of women)
 atypicals – risperidone does; clozapine does not

weight gain: up to 40% treated patients

Individuals with schizophrenia are at increased
risk for osteoporosis and fractures
◦ why: poor diet, lack of exercise, cigarette
smoking, and polydipsia
◦ Some antipsychotic medications may further
increase the risk of fractures by causing
dizziness, orthostatic hypotension, and falls.
•Studies in women with hyperprolactinemia (from pituitary tumors)
have demonstrated high rates of osteoporosis believed to result
from hypoestrogenism.
• Similarly, hyperprolactinemia in men results in hypogonadism
and bone loss.
• Preliminary surveys suggest that schizophrenia patients also
may have elevated rates of osteoporosis and pathological
fractures



hypotension
orthostatic hypotension
tachycardia

neuroleptic malignant syndrome
◦ characterized by rigidity, hyperthermia and autonomic
instability (hypertension and tachycardia)
◦ rare but potentially lethal reaction to neuroleptic
◦ onset can be sudden and unpredictable- usually
within first 2 weeks of drug
◦ incidence 1 – 2 %
◦ usually occurs early in onset of treatment
◦ txt – discontinue antipsychotic med and provide txt
for fever or cardiovascular symptoms – usually
intensive care - txts used to accelerate reversal of
condition – DA agonists
◦ Risk factors: young age, male, preexisting
neurological disability, dehydration, raid escalation of
dose, use of high potency meds or IM preps
Sedation
anti ACh
orthostatic
hypotension
EPS
chlorpromazine
++++
+++
++++
++
clozapine (*)
++++
++++
++++
+/0
fluphenazine
+
+
+
++++
haloperidol
+
+
+
++++
loxapine
++
++
+++
+++
mesoridazine
+++
++++
+++
+
olanzapine (*)
+++
+++
+++
+/0
Sedation
anti ACh
orthostatic
hypotension
EPS
perphenazine
++
++
++
+++
pimozide
+++
+++
++
++++
quetiapine (*)
++
+++
++
+/0
risperidone (*)
+
++
+
+
thioridazine
+++
++++
++++
+
thiothixene
+
+
+
++++
trifluoperazine
+
+
+
++
ziprasidone (*)
+++
+
+
++

wide therapeutic index and OD is seldom
fatal


Smoking rate in the general population - just
over 20 %
Smoking rate among schizophrenics - may be
as high as 90 %

Nicotine increases alertness.
◦ may enhance concentration, thinking and learning- benefit
due to illness or medication related cognitive problems.






Nicotine can help relaxation and can reduce anxiety
tension
Nicotine might have an antidepressant effect.
Nicotine may reduce positive symptoms, such as
hallucinations for a short period.
There is some evidence to suggest that smoking is
associated with reduced levels of antipsychotic
induced Parkinsonism.
Alter negative symptoms (?)
Smoking can help to relieve boredom and provide a
framework for the day.

Smoking can have an effect on
pharmacokinetics
◦ CYP P450 1A2- induced by chronic smoking – also
enzyme used for metabolizing certain
antipsychotics, including clozapine, fluphenazine,
haloperidol and olanzapine, thioridazine.
◦ This results in higher doses being needed.
◦ Smoking can also have an impact on the side
effects of medication.

keep up to date on current reviews….


150 studies – mostly short term - from all
parts of the world with a total of 21,533
participants.
Looked at double-blind studies◦ excluded open studies
◦ compare nine second-generation (atypicals) with
first-generation antipsychotics.
◦ examined symptom reduction; quality of life; side
effects such as movement disorders, weight gain
and sedation (sleepiness); and other factors.

Although quality of life was not reported in
most studies, the few that did report it
indicated that only amisulpride, clozapine
and sertindole improved patients’ quality of
life more than first-generation medications.


Amisulpride, clozapine, olanzapine,
quetiapine, risperidone, sertindole and
zotepine … more weight gain than
haloperidol
Clozapine, quetiapine and zotepine were
significantly more sedating than haloperidol,
while aripiprazole was significantly less
sedating than haloperidol.


All nine atypical antipsychotics caused fewer
movement disorders than the first- generation
medication haloperidol, which is highly potent.
However, when compared with low-potency,
first-generation medications such as
chlorpromazine and thioridazine, studies showed
that only a few atypical medications (clozapine,
olanzapine, and risperidone) caused fewer
movement disorders, but the low-potency drugs
also tended to induce weight gain and sedation
like the atypicals.



Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE)
assessed the effects of antipsychotic
medications on participants’ 10-year
coronary heart disease (CHD) risk.
examined atypicals - olanzapine (Zyprexa),
quetiapine (Seroquel) risperidone (Risperdal)
and ziprasidone (Geodon) and conventional
antipsychotic perphenazine.


standardized mortality ratios up to three
times those for the general population (Felker
et al., 1996; Brown, 1997).
Why?
◦ Increased suicide rates, increased accidental death,
increased smoking,
◦ cardiovascular disease?

Treatment of Early-Onset Schizophrenia
Spectrum Disorders (TEOSS)
◦ designed to rigorously compare the efficacy and
safety of a molindone (first generation), olanzapine
and risperidone (2nd generation), in the treatment of
early onset schizophrenia
◦ primary hypothesis: 2nd generation would show
greater treatment response and greater tolerability
◦ double-blind multisite trial; randomly assigned
pediatric patients with early-onset schizophrenia
and schizoaffective disorder


Sample:
119 youth randomly assigned to treatment.
◦ 116 received at least one dose of treatment

Results:
◦ NSD among treatment groups in response rates
(molindone: 50%; olanzapine: 34%; risperidone: 46%) or
magnitude of symptom reduction.
◦ Olanzapine and risperidone – significantly greater weight
gain. with Olanzapine showing the greatest risk of
weight gain
 significant increases in fasting cholesterol, low density
lipoprotein, insulin, and liver transaminase levels.
◦ Molindone led to more self-reports of akathisia.
PORT – Patient Outcomes Research Team