PHM142 Fall 2015
Instructor: Dr. Jeffrey Henderson
SCHIZOPHRENIA AND
ITS TREATMENT
Jenny, Fulbert, Tim, Carmen
Presentation
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Schizophrenia
Schizophrenia:
“a complex biochemical brain disorder [that] affects a person’s ability
to determine what is reality and what is not”
- Canadian Mental Health Association
https://i.ytimg.com/vi/hWMPI1zssDs/maxresdefault.jpg
Presentation
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Schizophrenia
Symptoms of Schizophrenia: 3
subtypes
1. Positive Symptoms
2. Cognitive Symptoms
3. Negative Symptoms
http://psychcentral.com/lib/treating-schizophrenia-successfully/
Presentation
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Schizophrenia
Symptoms of Schizophrenia: 3
subtypes
1. Positive Symptoms: things that
start happening
* Delusions/Paranoia
* Confused thoughts and speech
* others include: hallucinations,
repeating movements or
gestures, being indecisive, and
more
http://psychcentral.com/lib/treating-schizophrenia-successfully/
Presentation
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Schizophrenia
Symptoms of Schizophrenia: 3
subtypes
1. Positive Symptoms
2. Cognitive Symptoms: related to
processing information
* learning, using information
* trouble focusing or paying
attention
* memory problems
> may cause emotional distress
http://psychcentral.com/lib/treating-schizophrenia-successfully/
Presentation
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Schizophrenia
Symptoms of Schizophrenia: 3
subtypes
1. Positive Symptoms
2. Cognitive Symptoms
3. Negative Symptoms: things that
stop happening
* Wirthdrawal
* struggling with basics of daily life
* others include: “flat effect”
http://psychcentral.com/lib/treating-schizophrenia-successfully/
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Schizophrenia
So who is susceptible?
•
Everyone!
•
Typical age range:
*
> around the 20’s
*
> earlier for men than
women
•
Earlier symptoms = more
severe
•
very rare below age of 10
and above age of 40
http://spinewave.co.nz/wp-content/uploads/young-and-old.jpg
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Schizophrenia
Prevalence Rate
•
Worldwide: 1.1% of population over age of 18
•
In Canada, 1% of population (over 280,000 diagnosed)
- http://www.schizophrenia.com/szfacts.htm#
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Schizophrenia
Diagnosis of Schizophrenia
http://cdn1.bostonmagazine.com/wp-content/uploads/2013/01/diagnosis.jpg
•
USA criteria is two or more
of the symptoms, each
present for a significant
period of time within 1
month
•
Involves ruling out other
mental illnesses
•
Diagnosis of Schizophrenia
is complicated
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Schizophrenia
Hypotheses of Schizophrenia
1)
Classical Dopamine Hypothesis
2)
Serotonin Hypothesis
http://www.reach4resource.co.uk/node/120
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Schizophrenia
Dopamine Hypothesis
•
Excess dopaminergic activity
•
Illegal drugs that are
dopamine agonists induced
symptoms
•
PET reveals higher density of
D2 in striatum
http://www.nature.com/npp/journal/v35/n1/fig_tab/npp2009120f2.html
Schizophrenia
Complexity
•
Large studies on COMT
polymorphisms in twins had
no robust conclusion
•
Newer generation drugs had
systemic activity which
improve condition
•
High plasticity in brain
http://www.sciencedirect.com/science/article/pii/S016622361300
1148
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Schizophrenia
Serotonin
•
5-HT receptors are involved
in hallucinations
•
Serotonin agonists
exacerbate symptoms
•
Postmortem brains have
altered numbers of receptors
http://beadorigami.blogspot.ca/2013/04/beaded-serotonin.html
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Schizophrenia
Serotonin-Dopamine Hypothesis
•
Strong evidence indicating 5HT system modulating
dopaminergic activity
•
Interdependency
•
Combination of Hypotheses
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Schizophrenia
Introduction to FGAs
•
Typical, conventional,
classical antipsychotics
•
Dopamine antagonist
•
Chlorpromazine, Haloperidol,
Perphenzine, Thioridazine,
Loxapine, Trifuoperazine
http://www.kaefproduk.com/pic/CHLORPROMAZINE-415.jpg
Presentation
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Schizophrenia
Indications
•
Helps manage the positive
symptoms of schizophrenia
•
Controls or Reduces: anxiety,
agitation, problems with
thinking or remembering,
delusions and hallucinations
https://cdn.psychologytoday.com/sites/default/files/styles/imagearticle_inline_full/public/blogs/89816/2012/08/105118-102786.jpg?itok=5mOo2Tia
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Schizophrenia
Mechanism of Action
•
Not definitive
•
Antagonists of D2 Receptors
in the Mesolimbic Pathway
•
Positive symptoms of
Schizophrenia thought to be
due to over activity in this
pathway
http://psychopharmacologyinstitute.com/wp-content/uploads/2012/12/FirstGeneration-Antipsychotics-Mechanism-of-Action.png
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Schizophrenia
Classifications
Low Potency vs High Potency FGAs
1)
Low Potency – Greater anticholinergic,
antiseretonergic, antihistaminic, and α1/α2
antagonistic properties
2)
High Potency – Greater movement disorders (ex.
Tardive dyskinesia)
Presentation
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Schizophrenia
Chlorpromazine
•
Low Potency FGA
•
Acts on D2 receptors BUT
also: serotonergic,
histaminergic, α1/α2
adrenergic, muscarinic
receptors
https://upload.wikimedia.org/wikipedia/commons/thumb/e/ef/Chlorpromazine2DAC
S.svg/200px-Chlorpromazine2DACS.svg.png
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Schizophrenia
Chlorpromazine – Non anti-dopaminergic
Effects
•
Anti-cholinergic: dry mouth, blurred vision, obstipation,
difficulty/inability to urinate
•
Anti-adrenergic: hypotension, tachycardia, vertigo, sedation,
hyper-salvation
•
Anti-histaminergic: sedation, anti-emesis, vertigo,
hypotension, weight gain
•
Anti-serotonergic: anxiolytic, anti-depressive, anti-aggressive
properties, weight gain, hypotension, sedation, ejaculation
difficulties
Presentation
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Schizophrenia
Haloperidol
•
High Potency FGA
•
Less sedating, and anticholinergic side effects
•
Greater movement related
disorders (Extrapyramidal
Side Effects)
https://upload.wikimedia.org/wikipedia/commons/2/2e/Haloperidol_Str
uctural_Formulae.png
Presentation
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Schizophrenia
Haloperidol – Extrapyramidal Side Effects
(EPSE)
•
Blockade of D2 Receptors in the Nigrostriatal Pathway
•
Various movement disorders resembling Parkinson’s Disease (dystonia, akathisia,
parkinsonism
•
Tardive dyskinesia
•
•
Hyperkinetic movement disorder. Disorders in the movement of the face, tongue
and limbs
•
irreversible
Neuroleptic Malignant Syndrome
•
Rare but fatal
•
Extreme muscular rigidity, high fevers, coma, death
Presentation
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Schizophrenia
Treatment: Second Generation Antipsychotics
(SGAs)
•
First line choice
•
“atypical” antipsychotics:
greater affinity for 5-HT
receptors instead of D2,
•
Affects negative and cognitive
symptoms
•
Blocks D2 more moderately
compared to FGAs
http://childandmeds.blogspot.ca/; http://www.iconshock.com/icons/sunnyday/medical/treatment-icon.html
Presentation
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Schizophrenia
SGAs vs FGAs
•
SGAs generally has a broad
spectrum of activity
•
SGAs binds: dopaminergic,
serotonergic, muscarinic,
histaminic, and alphaadrenergic receptors
•
SGAs and FGAs have similar
efficacies in treating psychotic
symptoms
FGAs
SGAs
http://www.clipartbest.com/clip-art-scale
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Schizophrenia
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Schizophrenia
Side Effects:
•
Weight gain
•
Glucose abnormalities
(hyperglycemia, onset of type 2
diabetes, exacerbation of type 1
diabetes, diabetic ketoacidosis)
•
Hyperlipidemia, high blood
cholesterol
•
Orthostatic hypotension
•
Prolongation of QTc interval
http://www.clker.com/clipart-26448.html; http://biology.stackexchange.com/questions/2934/why-is-glucose-our-primary-source-of-energy; http://www.everylastrep.com/nutrition/7-natural-ways-preventhigh-cholesterol; http://ecancer.org/journal/3/full/130-qtc-prolongation-assessment-in-anticancer-drug-development-clinical-and-methodological-issues.php; http://ecancer.org/journal/3/full/130-qtcprolongation-assessment-in-anticancer-drug-development-clinical-and-methodological-issues.php
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Schizophrenia
Beneficial effects
•
Lower risk of suicides
•
Lower risk of extrapyramidal side
effects!
•
Lower risk of tardive dyskinesias,
hyperprolactinaemia
http://www.onlinemr.com/2011/12/03/the-secret-of-increasing-your-respondent-response-rate/; http://www.maryland-realestate-info.com/Lower-Real-Estate-InvestmentRisks; http://www.clipartpanda.com/categories/medal-clipart; http://hubpages.com/health/Sugary-Drinks-Cause-Disease-And-Sickness-In-People-With-Low-Body-Fat
Presentation
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Schizophrenia
Examples:
•
First line choices: Aripiprazole,
asenapine, lurasidone,
olanzapine, paliperidone,
quetiapine, riperidone, and
ziprasidone
•
Clozapine  treatment-resistant
schizophrenia
•
Risk of agranulocytosis (not
enough neutrophils made by
bone marrow)
http://www.drugsdb.com/blog/history-of-atypical-antipsychotics.html;
http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=104874;
http://www.youthhealthmag.com/articles/5188/20141217/antipsychotic-drug-geodon-could-causelife-threatening-skin-condition.htm
Presentation
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Schizophrenia
Low Occupancy Theory
•
Lower striatal D2 receptor
occupancy
•
Reduced affinity
•
Occupies 50% (gives clinical
response) to 80% (above
which causes EPS effects)
http://www.reach4resource.co.uk/side-effects?page=1
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Schizophrenia
“Fast Off” theory:
•
Short duration of binding, transient antagonism
•
Rapid dissolution rate of D2
•
Dopamine can still bind to some receptors
Presentation
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Schizophrenia
Two theories combine = moderate binding
•
SGAs
•
EPS effects
Moderate blockage
•
Antipsychotic effect with lower
EPS effects, hyperprolactinaemia
and tardive dyskinesia
•
Improves neuronal plasticity and
synaptic remodeling
No effects
http://thewordthoughtsblog.blogspot.ca/2014/04/moderate.html
Dopamine rises in the synapse
and competes with SGAs for D2
receptors.
Presentation
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Schizophrenia
D2 and 5-HT2A activity
•
Blockage 5-HT2A will increase
dopamine concentration in the
striatum synapses.
•
Dopamine can displace the SGAs
from the D2 receptors (fast off) to
reduce the risk of EPS.
•
The combined effect reduces
negative and cognitive symptoms
http://www.cnschronicle.com/2013/02/review-of-the-evidence-ofclozapines-anti-aggressive-effects/#
Presentation
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Schizophrenia
D2 Partial Agonism
•
SGA will bind to the receptor to
block dopamine from binding but
will still elicit an effect at the D2
receptors
•
Aripiprazole occupies 95% of the
D2 receptors and has much lower
activity here than dopamine (30%)
•
This results in a 65% blockade
(moderate which is key)
https://www.cnsforum.com/educationalresources/imagebank/dopaminergic
Presentation
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Schizophrenia
Summary
•
Schizophrenia is a complex biochemical brain disorder affecting a person’s ability to determine
what is real and what is not
3 subtypes of Schizophrenia symptoms include:
1. Positive: Symptoms which most individuals do not normally experience but are present
in people with schizophrenia. These include delusions, disordered thoughts and speech, and tactile,
auditory, visual, olfactory and gustatory hallucinations
2. Cognitive: deficiencies relating to information processing
3. Negative: deficiencies in emotional response
• The classical hypothesis for the cause of schizophrenia is excess dopaminergic activity in the
nigrstriatal pathway of the brain
• Schizophrenia has been shown to not be purely genetically linked (studies on twins showed no
robust conclusion)
• Multiple neurotransmitters, including dopamine and serotonin, have been linked to schizophrenia
• First generation antipsychotics help reduce the positive symptoms of schizophrenia by blocking
dopamine signaling in the mesolimbic pathway of the brain
• Second generation antipsychotics are the first line of choice to treat schizophrenia, and have a
broad range of activity (dopaminergic, serotonergic, muscarinic, histaminic, and alpha-adrenergic
receptors). These drugs include clozapine and olanzapine.
• SGAs have a lower EPS effects due to low occupancy and fast-off binding at the D2 receptor
Presentation
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Schizophrenia
References
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A Report on Mental Illnesses In Canada [Internet]. 2012. Public Health Agency of Canada; [cited 2015 Nov 27]. Available from:
http://www.schizophrenia.com/szfacts.htm#
Bobes, J., Garcia-Portilla, M. P., Bascaran, M. T., Saiz, P. A., & Bouzoño, M. 2007. Quality of life in schizophrenic patients. Dialogues in Clinical Neuroscience,
9(2), 215–226.
Schizophrenia: An Overview [Internet]. n.d. WebMD; [cited 2015 Nov 27]. Available from: http://www.webmd.com/schizophrenia/guide/mental-healthschizophrenia?page=1#1
Schizophrenia [Internet]. n.d. Canadian Mental Health Association; [cited 2015 Nov 27]. Available from: https://www.cmha.ca/mental_health/facts-aboutschizophrenia/#.Vkp2fbT8Gt8
Gaur, N., Gautam, S., Gaur, M., Sharma, P., Dadheech, G., & Mishra, S. (2008.). The Biochemical Womb Of Schizophrenia: A Review. Indian Journal of Clinical
Biochemistry, 307-327.
Antipsychotics for Treating Schizophrenia. (2014, November 14). Retrieved November 30, 2015, from http://www.webmd.com/schizophrenia/firstgeneration-antipsychotics-for-treating-schizophrenia
Chlorpromazine. (2014, April 4). Retrieved November 30, 2015, from http://www.drugbank.ca/drugs/db00477
First-Generation Antipsychotics: An Introduction. (2015). Retrieved November 30, 2015, from http://psychopharmacologyinstitute.com/antipsychotics/firstgeneration-antipsychotics/
Haloperidol. (2013, October 8). Retrieved November 30, 2015, from http://www.drugbank.ca/drugs/DB00502
Gaebel, W., Falkai, P., Weinmann, S., & Wobrock, T. (2006). Deutsche Gesellschaft für Psychiatrie PuNH (Hrsg) S3-Praxisleitlinien in Psychiatrie und
Psychotherapie, Bd 1: Behandlungsleitlinie Schizophrenie. Steinkopff, Darmstadt.
Stahl, S. M. (2008). Essential Psychopharmacology Online. Retrieved November 30, 2015, from
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Abi-Dargham, A., & Laruelle, M. (2005). Mechanisms of action of second generation antipsychotic drugs in schizophrenia: insights from brain imaging studies.
European Psychiatry, 20, 15-27.
Horacel, J., Bubenikova-Valesova, V., Kopecek, M., Palenicek, T., Dockery, C., Mohr, P., & Hӧsch, C. (2006). Mechanism of Action of Atypical Antipsychotic
Drugs and the Neurobiology of Schizophrenia. CNS Drugs, 20 (5), 389-409.
Brunello, N., Masotto, C., Steardo, L., Markstein, R., & Racagni, G. (1995). New Insights into the Biology of Schizophrenia through the Mechanism of Action of
Clozapine. American College of Neuropsychopharmacology, 13 (3), 177-213.
Presentation
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Schizophrenia