BIOLOGICAL BASIS OF BEHAVIOR
Psychology 321
Spring, 2005 HGH 225
Dr. John M. Morgan MWF, 8am to 9:00
Biological Basis of Behavior
Psychology 321
Spring 2005
Dr. John M. Morgan MWF 8am to 9am
Clozapine; an Atypical Anti-Psychotic Drug used in the treatment
of Schizophrenia
Justin Clarke: Introduction, chemistry of the drug, part of the
neuron effected, and the ion channels Clozapine reacts with.
Katrin Beene: Synaptic transmitters involved, inhibitory or
excitatory potential changes, and physiological changes.
Erin Averill: Primary behavior changes, side effect behavior
changes, and effects reported by users of clozapine.
Erin Averill
Primary Behaviors of Schizophrenia
Schizophrenia is defined as a "devastating psychotic
disorder that may involve characteristic disturbances in
thinking (delusions), perception (hallucinations), speech,
emotions, and behavior (Durand and Barlow 443). This disorder
effects nearly 2.5 million people.
The symptoms of schizophrenia are usually divided into two
categories, positive and negative. The positive symptoms
include delusions, hallucinations, disorganized speech or
thinking, grossly disorganized behavior, and catatonic
behaviors, which means that you suffer from motor immobility
(schizophrenia.com). Delusions are defined as a strong disorder
of thought and false beliefs of reality. There are five
categories of delusions. The first is persecutory in which a
person believes they are being attacked, harassed or conspired
against. For example, a person with persecutory delusions may
think that the government is spying on them. The second
category is grandiose delusions, which are defined as an
exaggerated sense of importance, power, and identity. For
example, a person may feel that they receive special powers from
God which gives them the ability to control things. The third
category is being controlled. This category of delusions
involves thoughts and feelings imposed from the outside. This
is sometimes referred to as "thought insertion." A person with
this type of delusion may feel that they are being controlled by
the devil or by a curse. The fourth category is somatic
delusions. These are defined as having false beliefs about
bodily functions such as having AIDS or being pregnant for three
years. The last category is jealousy which includes exaggerated
paranoias such as your spouse is cheating on you with the CIA.
Hallucinations are false perceptions. There are four
categories of hallucinations. The first is auditory which are
the most common. Auditory hallucinations are defined as hearing
voices or noises that don't exist. The second category is
visual, which is defined as seeing things that aren't there.
These hallucinations can be benign such as a flash of light or
scary such as monsters. The third category is tactile which are
hallucinations of touch. With these hallucinations the person
feels as if something is tickling them under their skin. The
last category is smells which are the least common
hallucinations. Often the smells are not pleasant.
The negative symptoms of schizophrenia are affective
flattening, alogia, avolition, and anhedonia. Affective
flattening is the lack of emotional expression. People who have
studied schizophrenia say that flat affect is like wearing a
mask. You can't show emotion when you are expected to (Durand
and Barlow 449). Alogia is described as poverty of speech or
decreased ability to formulate thoughts. Speaking to a person
with alogia can be extremely frustrating because they often give
short and uninformative answers to questions. Avolition is
defined as a loss of goal directed activities. "People with
this symptom show little interest in performing even the most
basic day-to-day functions including those associated with
personal hygiene" (Durand and Barlow 448). Anhedonia is a lack
of pleasure. A person exhibiting this symptom will be
uninterested in activities that they used to enjoy.
Schizophrenia is also marked by significant cognitive
impairments. These impairments include disorganized thinking,
slow thinking, difficulty understanding, poor concentration,
poor memory, difficulty expressing thoughts, and difficulty
integrating thoughts, feelings, and behavior. To be classified
as having schizophrenia a person must exhibit the afore
mentioned symptoms for six months with at least one month of
positive symptoms. These symptoms can not be due to
physiological effects or any other medical condition
(schizophrenia.com).
There are five subtypes of schizophrenia. Paranoid type is
characterized by a preoccupation with systemized delusions and
often auditory hallucinations. Their cognitive abilities are
relatively normal and they don't report any abnormal affect.
People diagnosed with paranoid type schizophrenia often have a
better prognosis than other forms of the disease (Durand and
Barlow 451). Catatonic schizophrenia is marked by psychomotor
disturbance. A person won't move or will posture which is like
posing. Another aspect of this type is called waxy flexibility
in which a person remains in fixed positions without resistance.
The third type of schizophrenia is disorganized. This type is
marked by grossly disorganized behaviors such as disordered
speech. They also exhibit inappropriate affect. People with
this type of disorder tend not to have marked delusions. People
who have undifferentiated type display prominent psychotic
features but do not fit into any other category of
schizophrenia. The last type of schizophrenia is residual.
People with this type have had at least one episode of
schizophrenia but no longer exhibit the major symptoms. More
commonly they are described as having "leftover" symptoms
including, social withdrawal, bizarre thoughts, or flat affect
(Durand and Barlow 451).
Schizophrenia is the most common ailment among the
psychotic disorders. There are several other psychotic
disorders that are similar to schizophrenia. Schizophreniform
involves symptoms of schizophrenia but the length of the
disorder is brief. In order to be classified as
schizophreniform the disorder must last less than 6 months.
This disorder affects about .2% of the population (Durand and
Barlow 452). Schizoaffective disorder features symptoms of
schizophrenia and a major mood disorder. According to the DSM-
IV-TR a person has to show prominent delusions and
hallucinations in the absence of mood disorder symptoms to be
classified as schizoaffective. Finally, a delusional disorder
features beliefs that are not consistent with reality. That is
they are experiencing delusions but have no other symptoms of
schizophrenia (Durand and Barlow 452).
Side Effects of Clozaril (Clozapine)
Novartis, a pharmaceutical corporation, manufactures
Clozapine under the brand name Clozaril. Clozaril is an
atypical anti-psychotic drug that works particularly well for
people who have not responded well to typical anti-psychotic
drug treatments. A person will also take Clozaril if the side
effects other drugs were unbearable. This drug was approved for
use in 1990 by the FDA (NAMI). Clozaril will treat both
positive and negative symptoms of schizophrenia and is effective
60% of the time (NAMI).
Common side effects of clozaril are sleepiness, dizziness,
constipation, excess saliva production (drooling) and weight
gain. Another adverse effect that occurs is orthostatic
hypertension which is when you blood pressure lowers while you
move from a sitting to a standing position. This could lead to
fainting. Another condition a person taking Clozaril make
experience is agranulocytosis. With this condition the white
blood cell count drops dramatically. A person can become
vulnerable to infections and unable to fight them off. However,
this condition is reversible by discontinuing the use of
Clozaril. Most doctors require a monitoring of white blood
cells of their patients who are on Clozaril.
Some patients report experiencing seizures. Along with
seizures cardiovascular and respiratory side effects may occur
but are uncommon.
Some other serious side effects may occur such as,
myocarditis (a swelling of the heart), cardiomyopathy (an
increase in size of the lower heart chambers), pulmonary
embolism (a clot blocks blood flow through the lungs), and
respiratory depression (NAMI).
Clozaril is different than typical anti-psychotic drugs in
that it produces virtually no extrapyramidal symptoms such as
tardive dyskinesia (TD). TD involves involuntary movements of
the mouth such as grimacing, sucking/smacking of lips (NAMI).
There have been no reported cases of TD by using Clozaril alone.
Personal Accounts of Schizophrenia
This first story is about Frederick Frese. His disorder
started with the development of a paranoia that enemy nations
had hypnotized American leaders. He also exhibited several
classic symptoms such as the inability to separate fantasy from
reality and hearing voices (schizophrenia.com). Later, he began
picturing himself as different animals, a monkey, dog or snake.
He was hospitalized for a few weeks then released. He wandered
the streets after that. He wandered the streets for a year
before he was arrested and put in jail. He finally was
transferred to a Veterans Administration hospital. This is
where he got real help. He was put on medication to control his
delusions. After that he was able to hold down jobs and he
received a masters and a PhD in psychology from Ohio University.
He went on to serve as director of psychology at the same
hospital that he had been a patient. He eventually got married
and had three children. He had a few relapses but now if he
starts to feel his symptoms worsen he increases his does of
Risperdal. Risperdal is similar to Clozaril in that it doesn't
cause the TD as seen in other anti-schizophrenic medications.
He has reported feeling some discrimination from family, friends
and employers. With the help of atypical anti-psychotic
medications he was able to live a relatively normal life with
many successes to report about.(schizophrenia.com)
The second story is about how a college student coped with
schizophrenia. His primary behaviors were believing that the TV
was talking to him and thinking that he was the Anti-Christ. He
ended up in the psychiatric ward. He got on medicine but still
felt like a "deer in the headlights." He had a hard time
keeping up with school and then his medicine failed and he was
hospitalized again. After the second hospitalization his life
turned around. He ended up finishing school with a degree in
Economics. He was also able to hold down several jobs. He has
tried every atypical antipsychotic medicine and they seem to be
working. People can overcome schizophrenia if they choose to
and can succeed in their own way and beat the odds.
References
Barlow, David H. and Durand, V. Mark. Essentials of Abnormal
Psychology. Thomson-Wadsworth, 2003.
Clozaril (clozapine). www.nami.org. 2/23/2005
Dr. Jim Dupree's class notes for Abnormal Psychology
Success Stories from People with Schizophrenia.
www.schizophrenia.com. 2/23/2005.
Katrin Beene
Clozapine: Neurotransmitters involved, inhibitory/excitatory
effects, physiological changes
Clozapine is an atypical anti-psychotic medication that
acts as an antagonist (a drug that blocks the effects of a
neurotransmitter), thus producing an inhibitory effect, at a
variety of neurotransmitter receptors in the brain. The exact
site and action by which Clozapine produces its therapeutic
effects is difficult to locate due to the complexity of its
interactions with several neurotransmitters. It is believed that
the two key neurotransmitters that Clozapine interacts with are
serotonin (5-HT) and dopamine (DA), particularly at 5-HT2, D2,
and D4 receptors (Brenner, H.D., BÖker, W., Genner, R., 2001).
Serotonin is a biogenic amine derived from tryptophan that
generally produces inhibitory postsynaptic potentials (meaning
that it causes hyperpolarization of the postsynaptic cell
membrane).Functions of serotonin include regulation of sleep and
emotions. Dopamine is a monoamine catecholamine derived from the
amino acid tyrosine. Receptors that bind dopamine are termed
dopaminergic. Dopamine is one of the principal modulatory
neurotransmitters in the brain and may have inhibitory or
excitatory effects depending upon the response of the
postsynaptic receptor (King, www.indstate.edu). Clozapine also
has effects at muscarinic M1 receptors, adrenergic receptors,
cholinergic receptors, and histamine receptors (Brenner, et al).
There are many disputed theories of the biological causes
of schizophrenia. One of the most prominent ideas is the
"dopamine hypothesis." The dopamine hypothesis attributes
hyperdopaminergic function, meaning an excess of dopamine at
certain synapses, as a possible cause of schizophrenia (Fann,
W.E., Karacan, I., Pokorney, A.D., & Williams, R.L., 1978).
Dopamine systems arise from two primary midbrain clusters, the
ventral tegmental area and the substantia nigra which have
discrete projections to mesolimbic, mesocortical, and striatal
regions of the brain. The neurochemical anatomy of dopamine
differs in cortical and striatal regions, and it appears that
dopamine concentration, receptor regulation, and D2 receptor
density varies greatly between striatal and extrastriatal
regions (Jones, & Pilowsky, 2002). It is supposed that the
therapeutic actions of antipsychotic drugs are exerted via the
mesolimbic and mesocortical dopamine pathways in the brain
(Hyman et. al., 1995). According to the dopamine hypothesis for
schizophrenia, limbic D2 receptor blockade is essential for a
drug to have antipsychotic activity. It is believed that the
therapeutic actions of antipsychotic drugs are exerted via the
mesolimbic and mesocortical dopamine pathways in the brain by
acting as D2 receptor antagonists (Hyman et al.)Without
exception, effective antipsychotic drugs have at least some
degree of antagonism of the dopamine D2 receptors. (Breier, A.,
Tran, P. V., Herrea, J.M., Tollefeson, G. D., Bymaster, F. P.,
2001).
Development of the atypical antipsychotic medication
clozapine challenged the dopamine hypothesis to a degree as it
is a relatively weak D2 receptor antagonist yet is still
therapeutically effective. Classic antipsychotic drugs occupy
80%-90% of D2 receptors while clozapine only occupies 20%-50% of
D2 receptors. Clozapine has a 10-fold higher affinity for the D4
receptor than for the D2 receptor (Hyman et. al., 1995). D4
receptors seem to be restricted to the limbic region and
clozapine preferentially binds to limbic rather than striatal D2
receptors (Henseik and Trimble, 2002)
Production of extrapyramidal side effects by typical drugs
seems to be due to the use of the drugs at doses where striatal
D2 receptor occupancy exceeds 80% (Strange, 2001). The term
"extrapyramidal"refers to the system of the basal ganglia and
brain stem nuclei by which they are connected. Extrapyramidal
side effects include Parkinson's-like tremors, akathesia (motor
restlessness), dystonia (prolonged muscle twitching), and
tardive dyskinesia (spasms of facial muscles). Clozapine is
considered an atypical antipsychotic due to its lack of
extrapyramidal side effects. Several reports indicate that it
improves or halts progression of tardive dyskinesia, chronic
akathisia, and drug induced parkinsonism (Lieberman & Salts &
Johns 1991). The lower affinity for D2 receptors may explain why
it does not cause significant extrapyramidal side effects and
explains why it does not increase prolactin levels. Another
hypothesis speculates that it may be clozapine's intense
anticholinergic potency that is responsible for the lack of
extrapyramidal side effects. It has been argued that the
simultaneous blockade of D2 and M1 receptors by atypical
antipsychotics may be much more effective in preventing
parkinsonism symptoms than non-simultaneous blockage. In yet
another hypothesis, the absence of extrapyramidal side effects
is attributed to atypical antipsychotics' greater affinity to
serotonin receptors. Clozapine has a high affinity for the 5-HT2
receptor. But serotonin antagonists don't seem to reduce side
effects in general.
Clozapine may cause few to no extrapyramidal side effects
but it has been known to produce other physiologic side effects,
the most serious being agranulocytosis. Agranulocytosis is a
potentially fatal hematological condition defined as an absolute
neutrophil count of less than 500/mm3 . Dramatic decrease of an
individual's white blood cell count can severely impair the
immune system causing a vulnerability to disease and infection.
Patients who are being treated with clozapine are required to
have a white blood cell count every week for the first six
months of treatment. Early symptoms of agranulocytosis include
weakness, lethargy, fever, sore throat, a general feeling of
illness, a flu-like feeling, or ulcers of the lips, mouth, or
other mucous membranes. More than 95% of cases of
agranulocytosis occur within the first six months of treatment,
with the period of highest risk between weeks four and eight.
The risk also appears to increase with age and may be higher in
women. There is evidence of clozapine accumulating in breast
milk so infants must be monitored along with their mothers for
hematological effects. The mechanism of agranulocytosis is not
known (Hyman, Arana, & Rosenbaum,1995).
The most common side effect associated with clozapine is
sedation and tiredness. During the first week some patients have
reported moderate fever with a feeling of physical illness.
Other adverse effects involving the central nervous system
include seizures (seen in up to 5% of patients with doses of 600
mg or more), vertigo, headache, disturbed sleep, restlessness,
slurred speech, agitation, and anxiety (Loeb, S., Blake, G.J., &
Hamilton, H.K., 1992). Most patients also experience weight
gain, generally attributed to a considerable increase in
appetite which is believed to be due to the depressing effect of
antipsychotics upon the satiety center of the hypothalamus
(Fann, et al., 1978).
Clinical EEG studies have shown that clozapine increases
delta and theta activity and slows dominant alpha frequencies.
Enhanced synchronization occurs and sharp wave activity and
spike and wave complexes may also develop. A small percent of
patients have reported an intensification of dream activity
while being treated with clozapine. REM sleep increased to 85%
of total sleep time, beginning almost immediately after falling
asleep (Loeb, et al., 1992).
Due to its anticholinergic properties, clozapine may affect
the cardiovascular system by increasing heart rate and
decreasing heart rate variability (Breier, 2001). Other
cardiovascular conditions associated with clozapine are
tachycardia, hypotension, and chest pain. Dermatological effects
may include a rash. Some of the gastrointestinal side effects
are constipation, nausea, vomiting, and dry mouth.
Hypersalivation occurs in most patients. This effect seems to be
dose related and is often excessive, at least initially.
Genital-urinary effects may include incontinence, abnormal
ejaculation, urinary frequency, and urine retention. Symptoms of
clozapine overdose are fast, slow, or irregular heartbeat,
hallucinations, restlessness, excitement, drowsiness, and/or
breathing difficulty (Loeb, et al. 1992).
References
Breier, A., Tran, P. V., Herrea, J.M.., Tollefeson, G. D., &
Bymaster, F. P. (2001). Current Issues in the
Psychopharmacology of Schizophrenia. Philadelphia: Lippincott
Williams & Wilkins Healthcare
Brenner, H.D., BÖker, W., Genner, R. (2001). The Treatment of
Schizophrenia- Status and Emerging Trends. Seattle:Hoegreffe &
Huber Publishers
Fann, W.E., Karacan, I., Pokorney, A.D., Williams, R.L., (1978).
Phenomenology and Treatment of Schizophrenia. Jamaica, NY:
Spectrum Publications, Inc.
Henseik, A.E., & Trimble, M.R. (2002). Relevance of new
psychotropic drugs for the neurologist. Journal of Neurology and
Psychiatry, 72: 281-285
Hyman, S.E., Arana, G.W., Rosenbaum, J.F. (1995). Handbook of
Psychiatric Drug Therapy Third Edition. New York: Little, Brown
and Company
Jones, H.M., & Pilowsky, L.S. (2002). Dopamine and antipsychotic
action revisited. The British Journal of Psychiatry, 181: 271-
275
King,M. www.indstate.edu.(Retrieved 2/15/2005). The Medical
Biochemistry Page
Lieberman J.A., Saltz B.L., Johns C.A. (1991).The effects of
clozapine on tardive dyskinesia. Journal of Psychiatry; 158:503-
10.
Loeb, S., Blake, G.J., Hamilton, H.K. (1992). Handbook of
Psychotropic Drugs. Pennsylvania: Springhouse Corporation
Strange, P.G. (2001). Antipsychotic Drugs: Importance of
Dopamine Receptors for Mechanisms of Therapeutic Actions and
Side Effects. Pharmacological Reviews, 53: 119-134
Justin Clarke- Biological Psychology Project 1
Clozapine, marketed by the trade name of "Clozaril," is a
member of the dibenzodiazepine class of antipsychotic
medication, and is one of many types of neuroleptic drugs.
Clozapine is an atypical medication because it differs from the
older conventional drugs such as Halodol or Lithium. The
difference between atypical and the older drugs is because there
less neuroleptic activity as a result of more specific receptors
utilized. The atypical drugs work effectively to treat
psychotic illnesses and tend to have fewer side effects than
their predecessors. Clozapine has been found to be the most
effective antipsychotic drug for treatment resistant
schizophrenia. Clozapine is used on a limited basis because of
the risk of agranullocytosis, where white blood cells are
destroyed faster than they are produced, causing the individual
to be prone to other illnesses. Two other drugs, either one
typical and one atypical, or two atypical medications are used
and deemed ineffective before clozapine is used due to the this
serious side effect, agranullocytosis. Even thought this risk
happens to be small, 1% to 2%, the drug is normally viewed in
the psychiatric field as a method of last resort.(Kentridge,
1995)
The most common explanation for what occurs in the brain of
a schizophrenic is the dopamine hypothesis, where certain areas
of the brain have excessive activity at certain dopamine
receptors.(Kalat, 2004) This theory will be a reoccurring theme
when explaining how clozapine interacts with the body. There
are also explanations dealing with clozapine's interaction with
the serotonin 5HT2 receptors and the glutamate receptors.
Initially patients are given a dose of 12.5mg on the first
day and on the second the dose is then doubled. If the drug is
tolerated by the patient the dosage is increased to 25mg to 50mg
a day until dose of 300mg is reached.(Naheed & Green, 2000)
Normally sedation isn't a problem because it only weakly
antagonizes apomorphine or amphetamine receptors.(Andreasen,
1994) Doses of Clozapine is absorbed very rapidly and peak
plasma levels are reached within 1-4 hours.(Kentridge, 1995)
The drug is spread through out the entire body and clozapine's
half life ranges from 5.5 to 33 hours. So in essence clozapine
reacts quickly in a patients body and the concentration remains
for a considerable amount of time. After 7 to 10 days a steady
concentration of plasma is normally reached, but the reduction
of anti psychotic features can take several weeks to become
effective and several months before the full therapeutic value
is obtained.(Naheed & Green, 2000) The amount of time it takes
this drug to work can be problematic because of the severity of
the disease and the likelihood that the patient will undergo a
severe psychotic episode. More than 40% of chronic
schizophrenics patients are poorly controlled by antipsychotics,
and then coupled with time the physiological processes need to
be theuraputic, clozaril and other neuroleptics can be difficlut
on the schizophrenic population.(Waddington & Buckley, 1996)
The areas of the brain that are effected by schizophrenia
are many, but significant correlations have been found with
abnormal brain activity and the Broca's area, Limbic, basal
ganglia, and paralimbic regions.(Mann, 1996) These areas are
related to sensory interpretation, processing and articulated
language, which are all linked to potential problems with
positive symptoms of schizophrenia. Clozapine reacts to neurons
in these critical areas of the brain and is thought to be why
clozapine and other neuroleptics are effective in treating
positive symptoms.
When examining the effects of clozapine on the neuron
level, the dopamine hypothesis suggests that the entire synaptic
area is mostly effected. The dopamine hypothesis explains that
there is an overabundance of dopamine, or an excess of dopamine
receptors, that causes schizophrenia. Since dopamine is one of
many neurotansmitters, the neuron could have several features
that lead to a disruption of effectiveness in schizophrenia.
Clozapine acts as an antagonist at the dopamine receptor in the
postsynaptic neuron. The drug binds to the dopamine receptor
and blocks the dopamine from binding to the dopamine
receptor.(Mann, 1996) The brain will compensate for the blocking
of receptors by creating more channels, this increases the
neurons sensitivity to dopamine to a more normal level.(Mann,
1996) Initially the brain and neuron compensate by increasing
dopamine synthesis, but this effect levels off after a week or
two. This explains why the clozapine takes several weeks to be
therapeutic, because the drug tinkers with the levels of
chemicals and time is needed to reach a normal amount of
dopamine.
There are Five dopamine receptors that have been discovered
that allow dopamine to bind to them and are called D1,D2,D3,D4,
and D5. The atypical neuroleptics are synonymous with how they
react specifically to the D2 receptor, and is why atypical drugs
are thought to have low incidences of extrapyramidal side
effects.(Mann, 1996) Clozapine differs from the other atypical
medications because it reacts a little less on the D1 and D2
receptor than the other drugs, but almost exclusively reacts to
the D4 receptor compared to other atypicals
neuroleptics.(Andreason, 1994) This is effected is believed to
be the reason why clozapine is an significant medication when
other medications failed to suppress the positive and negative
symptoms of schizophrenia. Also clozapine is one of the only
antipsychotic drugs that consistently reduce negative
symptoms.(Andreason, 1994) No valid link has been made with
clozapine and the D3, and D5 receptors in reducing psychotic
behavior, clozapine binds with these receptors, but it is
unclear as to what effect this might have.(Mann, 1996)
Another feature of Clozapine and how it binds with
receptors in the neuron is the receptor for serotonin,
especially the 5-HT1A and the 5-HT2. The explanation of this
process is unclear, but lack of this receptor has been found in
post mortem studies and is believed to be a strong explanation
to as how the schizophrenic mind works in addition to the
dopamine hypothesis. Clozapine has more potent antiserotonergic
effects than other antipsychotic medications. Higher 5-HT2 to
D2 receptors have been found in drugs that have limited
extrapyramidal side effects.(Andreason, 1994) Serotonin is not
the only reason for the reduction of side effects, because
typical neuroleptics like chlorpromazine also have this effect
on the 5-HT2, and chlorpromazine is associated with a high level
of side effects. So an interaction between D2, D4, and 5-HT2 is
hypothesized to be the reason for the reduction of
extrapyramidal side effects and successful levels of
interactions in the ion channels.(Andreason, 1994)
The glutamate receptors are another function of the brain
that is problematic in schizophrenia and effectively treated by
clozapine. Excessive dopamine levels in the synapse destroy
glutamate neurotransmitters, so schizophrenics have lower
activation of the glutamate receptors. Clozapine reacts by
reducing the amount of dopamine in the neuron enabling release
of more glutamate.(Andreason, 1994) Other muscarinic receptors
and GABA receptors show a similar reaction with dopamine levels
and increased levels after clozapine treatment. All of these
receptors have a quick turnover time so within a week levels
will increase with treatment of colazopine.(Naheed & Green,
2000)
Andreasen, N.C. (1994). Schizophrenia: From Mind to Molecule.
Washington, DC: American Psychiatric Press.
Kalat, J. (2004). Biological Psychology. 8Th edition, Chapter
15.3.
Kentridge, B. (1995). S2 Psychopathology Lecture 3:
Schizophrenia. Retrieved March 4, 2005. From
Http://www.dur.ac.uk/robert.kentridge/ppath3.html
Mann, R. (1996). The Role of Dopamine Receptors in
Schizophrenia. Retrieved March 3, 2005, From Stanford
University, Chemistry department web site,
http://www.chem.csustan.edu/chem44x0/SJBR/Mann.htm
Naheed, M., & Green, B. (2000). Focus on Clozapine. Retrieved
February 7, 2005. From http://www.priory.com/focus14.htm
Waddinton, J.L., & Buckley, P.F. (1996). The neurodevelopmental
Basis of Schizophrenia. Austin, TX: Landes Co.
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