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452 Chapter 17 Neurodegenerative diseases
PET scan/PET imaging: a diagnostic examination that involves the acquisition of functional images
based on the detection of positrons emitted from a radioactive substance administered to the
patient. Can be used to evaluate a variety of diseases.
Because PET is a functional imaging technique, it can detect alterations in biochemical processes
that suggest disease ahead of changes in anatomy detected using other imaging tests, such as
computed tomography (CT) or magnetic resonance imaging (MRI). CT and MRI brain scans of people
with Parkinson’s disease usually appear normal.
Diagnosis: Parkinson’s disease (stage 1)
Although it is impossible to predict what course Parkinson’s disease will take for an individual
person, one commonly used system is the Hoehn and Yahr scale.
Stage 1: Symptoms on one side of the body only.
Stage 2: Symptoms on both sides of the body. No impairment of balance.
Stage 3: Balance impairment. Mild to moderate disease. Physically independent.
Stage 4: Severe disability, but still able to walk or stand unassisted.
Stage 5: Wheelchair-bound, or bedridden unless assisted.
Plan: Commence pramipexole
Although there is no general consensus on when to initiate symptomatic treatment, it is often
begun when the patient begins to experience functional impairment as defined by:
• employmentstatus
• whetherthedominantsideisaffected
• severityofbradykinesiaand/orrigidity.
Andreas’s dominant side is affected and his symptoms are affecting his job.
Pramipexole, a non-ergot dopamine agonist, is chosen chiefly because of his age.
Eventually, Andreas will need levodopa-containing drugs and possibly other drugs as well. The
doctor wants to postpone using them because of their side effects and the short length of the
expected period of effectiveness.
1a) List three clinical conditions resulting from the death of neurons in the brain.
1b) What is the critical and common factor in these conditions?
2a) What is Parkinson’s disease?
2b) What part of the brain is affected in Parkinson’s disease? Abnormal cytoplasmic bodies/protein
deposits are found in the brain tissue post mortem. What are they called, and where in the brain are they
found?
3a) Which neurotransmitters are predominantly affected in Parkinson’s disease?
3b) How are they affected?
4a) List four symptoms of Parkinson’s disease experienced by Andreas.
WORKBOOK 14 Parkinson’s disease 453
4b) Non-movement disorder symptoms are associated with Parkinson’s disease. Give examples and
indicate how common they are.
4c) Try to identify which neurotransmitter systems in the brain might be responsible for these different
non-motor symptoms, and with this in mind try to suggest drug therapies that might alleviate these
symptoms.
When Andreas finally plucks up the courage to tell his wife Monique about his diagnosis, she is
distraught. He consoles her by repeating what he has been told by his neurologist.
Parkinson’s disease is not by itself a fatal disease, but does get worse with time.
The average life expectancy of a Parkinson’s disease patient is generally the same as for people
without the disease. The progression of symptoms may take 20 years or more.
There are many treatment options available for people with Parkinson’s disease.
He explains that he has been prescribed a drug called pramipexole, a dopamine agonist.
Monique has never come across the drug in her work as a medicine management technician
because she deals predominantly with cardiac, respiratory, or surgical patients.
Andreas tells her what he knows about the drug, which he has read up on. He explains that the
two main classes of drug used as first line for Parkinson’s disease are direct-acting dopamine
agonists, or levodopa (l-dopa) given together with a peripheral dopa-decarboxylase inhibitor.
5) Explain the mechanism by which dopamine agonists relieve the symptoms of Parkinson’s disease.
6a) What advantage do dopamine agonists have over levodopa?
6b) What is the advantage of non-ergot dopamine agonists over ergot dopamine agonists?
7) Why might longer-lasting agonists such as pramipexole be advantageous in reducing certain
unwanted side effects?
Andreas’ssymptomsimprovewithpramipexoleover3years,afterwhichtheystartresurfacing.
Treatment with levodopa is now necessary.
Almost all patients eventually require therapy with levodopa, which remains the most effective
pharmacological treatment for Parkinson’s disease, restoring dopamine levels in the brain and
thereby reducing symptoms.
Andreas is prescribed co-beneldopa (a combination of levodopa and a dopa-decarboxylase
inhibitor) to take alongside pramipexole.
8) What is the evidence that supports the theory that dopamine deficit is the cause of Parkinson’s
disease?
9a) Why is it necessary to give levodopa instead of dopamine?
454 Chapter 17 Neurodegenerative diseases
9b) What percentage of levodopa do you think gets to the brain after oral administration?
9c) What happens to the levodopa which does not enter the brain? Explain the roles of both dopa-
decarboxylase and catechol-O-methyltransferase (COMT).
10a) What is the other drug in co-beneldopa besides levodopa?
10b) What is its effect? Why is it administered together with levodopa?
10c) What is the effect of co-administration of COMT inhibitors on the delivery of oral levodopa to the
brain? Explain the mechanism.
After 1 year on co-beneldopa Andreas’s symptoms change in presentation. He feels very stiff
and can barely move before his morning dose.
11a) What do you think has happened?
11b) What treatment regime might improve this?
The doctor adds an extra dose of controlled-release co-beneldopa to be taken at bedtime. This
helps to alleviate the morning symptoms.
Three months later Andreas starts experiencing strange reactions 1–2 hours after taking his
medication. They include grimacing, lip smacking, and protruding his tongue.
12) List four side effects of levodopa.
The doctor decides to reduce the doses of Andreas’s medication, and to change the cobeneldopa entirely to a controlled-release preparation.
In addition to the neurologists, Andreas is looked after by several other professionals.
The pharmacist plays the following role:
• ensuringthatheunderstandstheroleofhisdrugsinthesymptomatictreatmentof
Parkinson’s disease and their possible adverse effects
• ensuringthatAndreasandhiscarersunderstandtheimportanceofcomplianceandtimingof
drug doses
• advisingonmethodsofimprovingandmaintainingcomplianceasthediseaseprogresses
and new drugs are added.
A psychotherapist is available to give emotional support. Andreas also finds the Parkinson’s
Disease Society very helpful.
Andreas starts feeling more depressed, and his GP decides to increase the dose of fluoxetine.
After a couple of months Andreas starts behaving strangely, and is diagnosed with levodopa-
inducedpsychosis.Tohelpwiththesepsychiatricsymptomsheisprescribedclozapine.
13) Why did the psychiatrist choose clozapine instead of, for example, haloperidol to treat the psychotic
symptoms? (See Section 17.3.3 and Chapter 18.)
WORKBOOK 14 Parkinson’s disease 455
Andreas’spsychiatricsymptomsarecontrolledwithclozapine,andthedyskinesiaimproves
with the reduction in dose and switching to a controlled-release preparation.
One year later, he experiences prolonged periods when he is again unable to move. The effect
ofhisdrugsalsoseemstobewearingoffafterabout3hours.
The doctor decides to replace the pramipexole with entacapone.
14a) To what class of drug does entacapone belong?
14b) What is entacapone’s mechanism of action?
14c) What are the adverse effects of this class of drugs?
Andreas improves following this switch from pramipexole to entacapone. He is, however,
worried about his options if and when his current medication becomes less effective.
He discusses his concerns with the consultant neurologist, who reassures him that there are
other drug options.
Andreas recalls from his pharmacology lectures that anticholinergics are used to treat druginduced parkinsonism.
15) Which class of drugs is commonly implicated as causing parkinsonism? How does this come about?
16a) Which symptoms of Parkinson’s disease will anticholinergics improve?
16b) Explain in detail how anticholinergics work to alleviate certain symptoms of Parkinson’s disease.
17) What are the side effects of anticholinergics?
Andreas asks the neurologist to give him some more information about selegiline and
rasagiline, which could have beneficial effects for end-of-dose deterioration. They discuss
selegiline as a possibility for Andreas. One issue the doctor mentions is that Andreas would
then have to discontinue fluoxetine.
18) Describe the mechanism of action of selegiline.
19) Why should selegiline be taken in the morning?
20) Why should selegiline not be taken with fluoxetine? Set out the mechanisms and consequences of
this drug interaction. (See Chapter 19.)
Amantadine and apomorphine are also options for Andreas.
21a) What are the suggested beneficial mechanisms of action of amantadine in Parkinson’s disease?
21b) What is the mechanism of action of apomorphine? When is it commonly used?
22) Describe some novel treatments for Parkinson’s disease and the basis for their use.
Chapter 18
Schizophrenia
Useful terms for this topic
Cognitive symptoms: Symptoms relating to disorders
in thought processes, including attention, learning,
social interactions, reasoning, and memory.
Dystonia: Muscle spasm and abnormal posture.
Extrapyramidal effects: Antipsychotic-induced motor
side effects including a syndrome that resembles
Parkinson’s disease.
Negative symptoms: Impairment of normal
functioning including loss of motivation, social
withdrawal, lack of energy, and emotional blunting.
Positive symptoms: Psychotic symptoms including
paranoia, hallucinations, and delusions.
Tardive dyskinesias: Involuntary abnormal
movements of the tongue, jaw, and lips.
e onset of a schizophrenic episode is often a confusing,
distressing, and anxiety-provoking time, particularly if
this is the rst such experience. Schizophrenia commonly
presents in young adults, and so the primary symptoms,
and the disorientation which follows, can be
superimposed on adolescent insecurities and lack of
condence. e individual may not, in such
circumstances, be well placed to assess and choose
between the various support services and therapeutic
options on oer. e families of young adults presenting
with schizophrenia may share in this distress and anxiety;
parents may be horried at the suering of their ospring,
fearful for the future, and experience feelings of guilt at
being bad parents or having passed on bad genes.
In Workbook 15 at the end of this chapter we meet Shaun,
a seriously distressed young man with bizarre and
disruptive behaviour. Despite medical intervention he
continues to have psychotic episodes spread over a
number of years. He tries a number of dierent
antipsychotic drugs until a solution is reached for him
that largely controls his symptoms without unacceptable
and unwanted eects. However, over the few years for
which we follow his story he seems unable to remain
symptom free without his antipsychotic medication. His
troubles are not uncharacteristic of such patients. As for
his long-term prospects—well, schizophrenia is a chronic
condition. However, there is every reason for optimism
that with continued medication the burden of
schizophrenia can be reduced, and it is possible that he
may be one of those who, given time, is able to stop his
drug therapy and remain symptom free.
In schizophrenia the cause, severity, and symptoms vary
between patients. e long-term outcome is also variable
and is likely to depend on many factors. ese include the
broader issues of non-pharmacological treatments and
support services that are oered to the patient. Non-drug
treatment is likely to play a major part in the management
of the condition, and the balance between drug and
non-drug therapies will vary with the patient and the
doctor/therapist.
In this chapter we focus on drug treatment for
schizophrenia, and particularly on the action of drugs at
the cellular and molecular level. At their best these drugs
restore a working balance between dierent
neurotransmitter systems in the brain; which particular
neurotransmitters, and how they are aected, depends on
the individual drug being used. Our understanding of
these issues is imperfect, but we can begin to place the
clinical use of dierent classes of antipsychotic drugs
within a scientic framework. Despite the incomplete
knowledge we have of the neurobiological cause of
18.1 What is schizophrenia? 457
schizophrenia, drug action still provides the foundation
for a rational approach to therapy. In addition, the focus
on cellular events in the brain, the neurotransmitter
approach, enables us to briey consider the prospects for
fundamentally new drugs in the treatment of this
destructive disorder.
18.1 What is schizophrenia? Symptoms, diagnosis, and causes
Schizophrenia varies between individuals, but common
to all is a pattern of disordered thinking. is may be
observed as clusters of symptoms, which are classied
and described in a variety of ways.
18.1.1 Symptoms of schizophrenia
e disordered thinking of schizophrenia can be
organized into dierent groups (Figure 18.1).
Disorder of form
Disordered stream of thought
resulting in
… incoherent and
meaningless speech,
… a jumble of words,
… disorganized sentences,
… ‘talking rubbish’
• Disorder of form Apparent as an incoherent speech
pattern, jumbled words or disorganized sentences,
reecting a disordered stream of thought.
• Disorder of content For example, a patient may believe
that his/her thoughts are being broadcast and can be
heard by others, or that thoughts are being directly
inserted into his/her head by other people or inanimate
objects. e patient may suer from delusions, such as
Disorder of content
e.g. belief that
… thoughts are being broadcast
to others
… thoughts are being inserted into
head
… delusional thoughts (e.g. of power)
… belief that inanimate objects are
alive
Positive symptoms
Bizarre, disturbed,
agitated, aggressive,
deranged, paranoid
behaviours and
beliefs;
hallucinations.
These respond well
to antipsychotic
drugs
Figure 18.1 Disorderedthinkinginschizophreniageneratesaspectrumofsymptoms.
Patients vary considerably in the balance between these symptoms.
Cognitive symptoms
Can’t make sense of the
everyday world. Can’t link
thoughts and outside events,
can’t understand normal
behaviour in others, etc.
Negative symptoms
Lack of response to
good/bad things, lack
of interest, poverty of
speech, social
withdrawal.
These respond
poorly to
antipsychotic drugs
458 Chapter 18 Schizophrenia
inated importance or power, and exhibit delusional
behaviour.
Symptoms may include the following.
• Hallucinations, principally auditory, such as hearing
voices which may be telling the patient what to do,
including self-harming or harming others.
• Flattening of aect refers to a withdrawn individual
not showing normal responses to the good or bad
events of everyday life, perhaps resulting in poor
personal care. e patient may appear to lack normal
emotional responses.
• Motor behaviour disorders: movement may be
reduced (sitting in a stupor), raised (excitable), or
dysfunctional (e.g. aimless or clumsy movements).
Added to this, the drugs used to treat schizophrenia
may themselves cause motor dysfunction.
• Avolition: an inability to initiate and sustain goal-
directed activities.
Some people may continue an apparently undisrupted
everyday life despite suering from a cluster of these
characteristics. For other individuals the consequences
may include an inability to make sense of the world,
bizarre and disruptive behaviour leading to social
withdrawal, fearful and angry responses, and failure to
attend to work or educational needs.
e symptoms above may be divided into the following.
• Positive symptoms, which are those associated with
madness, such as jumbled speech, hearing voices,
paranoia, belief in thought insertion, or delusions of
grandeur. Hallucinations, when present, are likely to be
auditory (contrasting with the visual hallucinations
caused by hallucinogens such as LSD).
• Negative symptoms such as lack of aect, lack of
interest in everyday life, and apparent lack of emotion.
• Cognitive symptoms which derive from poor
concentration and memory, and diculty in
integrating thoughts, resulting in diculty in
understanding events and people.
e distinction between positive and negative symptoms
is important when we consider medication because:
• negative symptoms are generally hard to treat
compared with positive symptoms
• it is often positive symptoms that result in hospitalization;
however, resistant negative symptoms, which can persist
on discharge from hospital even with antipsychotics, may
signicantly impair ability to function
• some drugs, however, are better at reducing negative
symptoms than others.
Notably, negative symptoms in some patients may
worsen with time. is deterioration may be reduced with
early therapeutic intervention.
18.1.2 Diagnosis of schizophrenia
Other medical conditions and substance abuse that could
account for the behaviours and symptoms must be
excluded early in the investigation. In Workbook 15 we
see that Shaun has blood tests in hospital. ese are to
exclude other conditions—there is no reliable blood test
for schizophrenia.
Schizophrenia varies a lot from one patient to another,
making consistent diagnosis dicult. Criteria for
diagnosing schizophrenia come from the Diagnostic and
Statistical Manual of Mental Disorders (version DSM-IVTR) and the International Statistical Classication of
Diseases and Related Health Problems (ICD-10).
Diagnostic schemes are likely to require all of the
following to be present.
1. A minimum of two symptoms from:
a) delusions
b) hallucinations
c) disorganized speech
d) grossly disorganized catatonic behaviour
e) negative symptoms (poverty of speech, absence of
emotions)
f) avolition (inability to initiate and sustain goal-
directed activities).
2. Social/work/school disruption.
3. Duration of at least 6 months.
Elements of each of these three symptom clusters are
illustrated in the case of Shaun in Workbook 15.
18.1.3 Causes of schizophrenia
e origins of schizophrenia have been the subject of
much research and are still unclear, and mostly beyond
the scope of this text. However, some brief observations
are useful. ere are multiple causes of schizophrenia.
e simplest way to divide the causes is into
environmental and genetic (Figure 18.2).
Environmental inuences start in the womb and are
dominated by the functioning of the family during
childhood. Genetic inuences involve the combination of
18.1 What is schizophrenia? 459
INHERITANCE
Total
population
1%→→→→→→→17%→→→→→→→ 46%
Lifetime risk of developing schizophrenia
(notably family, but also perhaps wider social
conditions, birthing, viral infections etc.)
Figure 18.2 The interplay between inheritance and environment in the
causesofschizophrenia.
Schizophrenic
sibling
ENVIRONMENT
From infant to young adult
inherited genes. While it is possible that research will
discover a ‘schizophrenia’ gene, this seems most unlikely.
What you inherit is a propensity for schizophrenia, and
this in itself is likely to be polygenic, i.e. to involve an
ensemble of interacting genes. Whether an individual
develops schizophrenia depends on both environmental
inuences and the inherited propensity to develop this
condition. e signicance of an inherited component
can be seen in the prevalence of schizophrenia. is is
about 1% (lifetime risk) in the general population, about
17% if there is a schizophrenic brother or sister, and about
46% if in addition both parents suer from the condition
(Figure 18.2). Of course, siblings and parents mostly live
within the same family, and so we must assume that the
common environmental inuences contribute to these
family clusters. However, a comparison of identical and
non-identical twins is helpful. If one is schizophrenic then
in identical twins (where the genetic make-up is identical)
there is a 46% risk of the other twin developing the
condition. is is compared with about 17% for nonidentical twins (the same relative risk as for non-twin
brothers or sisters). ese and many other types of studies
have established the view that the causes of schizophrenia
include a complex interaction of inheritance and
environmental/developmental inuences.
18.1.4 A biological basis for
schizophrenia?
ese issues (genetic and environmental) have an
inuence on the way we view the treatment of
schizophrenia with drugs. If a patient has an inherited
Both
parents
or
Identical
twin
developmental decit, this may lead to abnormalities in
structure, neural network, or neurotransmitter balance in
the brain that we can dene with a biological theory for
schizophrenia. e most inuential biological theory
relates to an overactive dopaminergic inuence in
specic brain regions. It is the ventral tegmental–
corticolimbic system (system 3 in Figure 18.3) that is most
important in schizophrenia. e dopamine pathways and
receptors in the brain are further described in Box 18.1. In
Box 18.2 the dopamine hypothesis for schizophrenia is
discussed, together with the glutamate theory. We note
that there are other neurotransmitter-based theories
relating to schizophrenia (see Section 18.2.2), and also
theories derived from structural and functional studies
that are not related to a particular neurotransmitter. With
our focus on drug action the neurotransmitter-based
theories are the most helpful, since we can then try to
correct this neurotransmitter imbalance with targeted
drugs with some expectation of success in terms of
clinical benet.
If we reject the notion of a biological cause, it is not
necessary to reject the benets of drug therapy, or of the
importance of developing better drugs, but expectations
of resolving the diculties of schizophrenic individuals
with drug therapy will be lower. What the summary of
drug actions below tells us is that a biological answer is
unlikely to be simple. Advances in drug discovery are of
enormous importance in improving the prospects for
schizophrenic individuals, but drug treatments also suer
from disturbing pitfalls, as illustrated in Workbook 15 in
the case of Shaun.
Box 18.1
Brain dopamine pathways and dopamine receptors
e central feature which all antipsychotic drugs have
in common is that they act as antagonists of dopamine
receptors. For this and other reasons it has been
suggested that the symptoms of schizophrenia may be
caused by dopamine overactivity in certain parts of
the brain (see Box 18.2).
ere are two main ascending dopamine pathways in
the brain and one short projection. ese are
illustrated in Figure 18.3.
e nigrostriatal system is the densest dopamine
system in the brain. e substantia nigra comprises a
compact collection of cell bodies that send a large
number of axons up into the areas designated as the
striatum (also referred to as the caudate and putamen)
and the globus pallidus. Here the densely packed
dopaminergic terminals contain the highest
concentration of dopamine in the brain. ese
terminals form synapses with a variety of cell bodies,
including those of intrinsic cholinergic neurons.
e other main ascending system, the corticolimbic,
has cell bodies in the ventral tegmental area that send
their axons upwards to the limbic and cortical areas,
which are associated with emotions, reward, and
other higher brain functions. Not surprisingly this is
the system implicated in schizophrenia.
In addition to these two major ascending systems
there is a short projection within the hypothalamus,
located at the base of the brain near the pituitary. is
projection is sometimes called the tuberoinfundibular
system. e cell bodies are located in the arcuate
nucleus (the tuberal region) and send short axons
down to the median eminence (the infundibular
region) at the base of the hypothalamus. e
dopamine released here acts to inhibit the release of
prolactin from the anterior pituitary.
Dopamine receptors
Dopamine acts on a family of receptors designated
D1–D5. ese are all coupled via heterotrimeric G
proteins to enzymes and ion channels (see Chapter 2),
which together regulate neuronal function. To
understand the evolving characteristics of
antipsychotic drugs it is necessary to have some
understanding of this family of receptors and their
location within dierent brain regions.
D1 dopamine receptors are very abundant in all
main dopamine projection areas. Dopamine acting on
these receptors results in the stimulation of cyclic
AMP synthesis, with diverse downstream
consequences. D1 receptors are the main dopamine
receptors within the prefrontal cortex.
D2 dopamine receptors are also abundant in the
main dopamine projection areas—they are
particularly important for the action of antipsychotic
drugs, with respect to both wanted and unwanted
outcomes.
D3 and D4 dopamine receptors are overall much less
abundant than D1 and D2 receptors, and are
preferentially located within the ventral tegmental to
corticolimbic projection areas, but not in the
nigrostriatal areas. is is a potentially important
dierence for the action of antipsychotic drugs, since
it suggests the possibility of specic regulation of
corticolimbic functions independent of nigrostriatal
movement control. D3 receptors are particularly
abundant in the prefrontal cortex.
D5 dopamine receptors show similarities to D1
receptors, but are of lower abundance with some
concentration within corticolimbic areas.
D1-like and D2-like families D1 and D5 receptors can
be grouped together and considered as D1-like. Both
receptor subtypes are coupled through Gs to an
increase in cyclic AMP synthesis. D2–D4 dopamine
receptors can also be clustered into a D2-like family.
ey are all linked to the inhibition of cyclic AMP
synthesis, the activation of K+ channels and the
inhibition of Ca2+ channels. All of these actions can
be summarized as dampening down neuronal
activities and opposing the eects of D1 receptor
activation.
Implications for antipsychotic drug therapy e
following comments can be considered together with
those set out in Section 18.2.8.
Box 18.1 Brain dopamine pathways and dopamine receptors
• In the search for drugs treating both negative and
positive symptoms of schizophrenia, it is tempting
to imagine that the objective is a highly selective
drug acting at either D3 or D4 receptors. Such a drug
should be devoid of signicant nigrostriatal eects,
and thus free of extrapyramidal1 side eects.
• More selective D4 antagonists have indeed been
produced, but this has not led to the predicted
improved outcome.
• Selective D3 antagonists are being developed.
• D3 and D4 receptors have mainly corticolimbic
distribution, but even in this area D1 and D2
1
You will frequently encounter the term ‘extrapyramidal’ in accounts
of the unwanted movement eects of antipsychotic drugs. Movement
instructions from the cortex pass through the ‘pyramids’ in the
brainstem on their way down to the spinal cord and the motor
neurons. e extrapyramidal system, which modulates and plans
movement control, does not pass through these brainstem ‘pyramids’,
but it does pass through the striatum (caudate/putamen). is
extrapyramidal system depends on a suitable dopamine input from
the substantia nigra to the striatum to function properly, and it is this
which is disturbed in Parkinson’s disease and by the dopamine
antagonists used to treat schizophrenia
receptors are more abundant. is suggests that D3/
D4 manipulation will only oer a small part of the
potential for control of dopamine inuences in
these brain regions.
• It is now understood that a degree of agonist activity
at certain receptor subtypes (e.g. D1) also
contributes to the therapeutic response for some
drugs.
To sum up, it is likely that D2 antagonism will remain
the cornerstone of antipsychotic drug therapy. In the
future, an improved therapeutic outcome for
schizophrenic patients is likely to involve drugs
which also act at additional dopamine receptor
subtypes, as well as at receptors for other
neurotransmitters (e.g. serotonin and glutamate).
While we can see some of the features of this
landscape, there are still too many unknowns to be
able to make the therapy an exact science. Hence the
trial-and-error aspect to the prescribing of
antipsychotic drugs, as illustrated by the
management of Shaun’s illness in Workbook 15.
18.2 Drugs in clinical use for the treatment of schizophrenia
Over 20 dierent drugs are currently available for the
routine treatment of schizophrenia. Each varies in
eectiveness against particular categories of symptom
and in the likelihood of unwanted eect. ese
dierences include:
• a sedative eect—positive with agitated patients,
unwanted in others
• attenuation of positive symptoms—of widespread
value for schizophrenic patients, both in the short term
for those with acute exacerbations and in long-term
maintenance
• eectiveness in treating negative symptoms—of
widespread importance, but many antipsychotic drugs
are ineective in this regard
• a risk of producing adverse movement eects—often
referred to as extrapyramidal side eects
• antimuscarinic eects, with some drugs being potent
muscarinic acetylcholine antagonists.
To some degree these variations in clinical outcome can
be understood in terms of the dierent interactions with
receptors found in the brain. e starting point for such
considerations is the interaction of drugs with the
dopamine receptors.
18.2.1 Antipsychotic drugs are dopamine
antagonists
All antipsychotic drugs in clinical use are antagonists
at dopamine receptors, an action that is important for
their therapeutic effect. The location of the three main
dopaminergic neuronal systems in the brain, and the
receptor subtypes involved, are depicted in Figure 18.3
and discussed in Box 18.1. Understanding how
different drugs produce their particular spectra of
wanted and unwanted effects requires a broad
appreciation of the functions of these three neuronal
systems, as well as of the receptor subtypes targeted by
the drugs.