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472 Chapter 18 Schizophrenia
Therapeutic
group
Atypical
antipsychotic
drugs
Class/drugs Mechanism of action Common clinical uses Comments Common adverse drug
Olanzapine
Quetiapine
Risperidone
Paliperidone (metabolite of
risperidone)
Sertindole
Zotepine
Aripiprazole Partial agonist activity at
Clozapine Weak antagonist at D1,
Block both dopamine and
5HT2A receptors
Greater affinity for 5HT2A
than dopamine receptors
D2 and 5-HT1A receptors
and antagonist at 5-HT2A
receptors
D2, D3, and D5 receptors,
and high potency at D4
receptors
Antagonist at -adrenergic,
cholinergic, histaminergic,
and serotonergic receptors
Schizophrenia
Mania
Psychoses
Schizophrenia
Mania
Schizophrenia Reserved for third-line use
Metabolized by hepatic
CYP3A4 and CYP2D6
(P450) enzymes leading to
interactions
Patients need close
monitoring of full blood
count
reactions
Weight gain
Dizziness
Postural hypotension
Sleep disturbances
Agitation
Anxiety
Akathisia
Tremor
Dizziness
Somnolence
Sedation
Headache
Blurred vision
Agranulocytosis
Myocarditis
Myopathy
GI obstruction
WORKBOOK 15
Failure and success in long-term drug
treatment
Shaun develops a serious mental illness as a young man
The patient: a simplified case history
Tom, the warden of the university hall of residence, has finally decided to call the police, after
learningthatShaun,asecondyearstudent,hasbeenroamingaroundinsub-zero
temperatures, wearing nothing but his ripped boxers and sandals. Earlier, after smashing his
computer because ET, his alien friend, had ordered him to, Shaun had jumped out of a second
floor window because ‘they’ were after him. When Tom eventually finds him, Shaun becomes
aggressive and pushes him away.
In the student bar he begins shouting that aliens have invaded, and that he, Shaun, is going to
be king of the new planet. After a struggle, Shaun calms down and agrees to be taken to the
psychiatric hospital on the recommendation of a psychiatrist contacted by the police. His
flatmate Billy agrees to be interviewed about recent changes in Shaun’s personality.
A table of clinical clerking abbreviations is given on page xviii.
CLINICAL CLERKING FOR SHAUN AT PSYCHIATRIC
ADMISSIONS WARD
Age and gender: 23-year-old male student
PC: Frightened and aggressive young man who jumped from second floor window, running around half-
naked in January cold, talking about aliens and spies in incoherent sentences.
HPC: Over the last 7 months Shaun has completely changed from a well-presented sociable student,
to an isolated, antisocial, and unkempt person. Suffering delusions and hallucinations (both visual and
auditory); speech is jumbled and erratic.
PMH: Nil significant
Mental status examination:
Delusions: Shaun thinks he will be king of the new world, and that everyone is out to get him.
Hallucinations: He apparently sees and speaks to aliens, and hears voices from his TV giving him
instructions.
474 Chapter 18 Schizophrenia
Speech: Shaun speaks rapidly, jumping from topic to topic within a single sentence. For example,
during interview he says, ‘ET will get my shoes, you are reading my mind, listen they will destroy you’.
He is unable to answer simple questions accurately; his responses are long-winded and only loosely
connected to the question.
Negative symptoms: He is unable to concentrate in class. When he is not rambling incoherently, his
speech is brief and lacks spontaneity.
Social/occupational dysfunction: Shaun does not socialize any more and has given up his part-time
job. He has the appearance of an unkempt young man with poor hygiene.
Duration: Shaun has had these symptoms longer than 7 months.
Exclusion of schizoaffective and mood disorder: These have been ruled out in Shaun’s case from
his history, and following interviews with him and his flatmate.
Substance abuse: Shaun’s urine sample has tested negative.
Relation to a pervasive developmental disorder: The psychiatrist rules this out.
Mental status examination is used most commonly to diagnose suspected schizophrenia, and is
based on two systems of classification:
• DiagnosticandStatisticalManualoftheAmericanPsychiatricAssociation,textrevision
(DSM-IV-TR)
• InternationalClassicationofDiseasesandRelatedHealthProblems,10thRevision(ICD-10).
By using criteria adapted from these systems, psychiatrists are less likely to misdiagnose
schizophrenia, because they are prompted to take the whole clinical course, and not just the
presenting symptoms, into account.
Overview of diagnostic criteria:
1) Characteristic symptoms: minimum of two, present for 1 month
Delusions, hallucinations, disorganized speech, grossly disorganized behaviour, negative symptoms:
poverty of speech, absence of emotions, avolition (inability to initiate and sustain goal-directed
activities).
2) Social/occupational dysfunction
Positive if dysfunction is present over a considerable period in at least one of these areas: work,
interpersonal relationships, or self-care, and is significantly worse than before onset of symptoms.
3) Duration: continuous signs persist for more than 6 months.
4) Schizoaffective and mood disorder exclusion
Rule out major depressive, manic, or mixed manic episodes as cause of symptoms.
5) Exclusion of substance abuse and general medical conditions
Rule out substance abuse or medical condition as cause of symptoms
A positive test could complicate diagnosis for the following reasons:
a) Use of cannabis and other substances (e.g. PCP, ketamine, LSD; see Chapter 21) can cause
psychotic episodes which can be indistinguishable from schizophrenia
b) Cannabis can improve the negative symptoms of schizophrenia, and is sometimes used
illegally as self-medication by schizophrenics
WORKBOOK 15 Failure and success in long-term drug treatment 475
6) Relation to a pervasive development disorder: Does the patient have a history of a disorder such
as autism?
TheoutcomeofShaun’smentalstatusexaminationindicatesschizophrenia.
Full blood count: Nil significant
Abnormalities in components of the blood could indicate that Shaun’s symptoms are due to a
physical illness; it is important to exclude this possibility. Since Shaun’s test showed nothing of
significance, it can be concluded that he is physically healthy.
Thyroid function test: Nil significant
Liver function test: Nil significant
Neurological examination: Unremarkable
Psychosocial history: After investigation the team found that Shaun had been brought up by his
grandmother. His mum had left when Shaun was a baby. His dad, suffering from recurrent psychotic
episodes, had been unable to look after him.
Differential diagnosis: Schizophrenia
Shaun has most of the classic symptoms of schizophrenia
His symptoms will be used to assess and monitor his response to treatment.
Problems with diagnosing schizophrenia
Evenusingthecriteriaabove,todiagnoseapatientassufferingfromasingleunderlyingdisorder—
schizophrenia—remainsamatterofcontroversy.Diagnosiscanalsobecomplicatedbythefollowing
factors.
1) Some doctors in both primary and secondary care are reluctant to make such a diagnosis, and
could as a consequence delay treatment.
2) Given the stigma that surrounds the illness and the diagnostic uncertainties, some patients and/
or their families are reluctant to accept a diagnosis of schizophrenia.
Shaun refuses to accept treatment or to stay in hospital. The team decides to admit him under
Section2oftheMentalHealthAct1983.
Section 2 of the Mental Health Act 1983 is an order for involuntary admission for assessment, for a
maximum of 28 days. It is used when an individual is thought to suffer from mental disorder and to
present a risk to themselves or others, but refuses to be admitted to hospital voluntarily, when this
is believed to be the best option. Two medical recommendations are required, and one must be from
an accredited psychiatrist. Both recommendations have to be agreed by an approved social worker,
who then makes an application for the section.
These procedures for compulsory admission apply to the UK only, but many other countries have a
similar system.
476 Chapter 18 Schizophrenia
Plan:
1) De-escalation and medication
De-escalation refers to structured reassurance and support in a tranquil environment. It is used to
treat sufferers in acute crisis before, and alongside, drug treatments. In extreme situations, where
patients pose an immediate risk of harm to themselves or others, physical restraint techniques and
controlled seclusion environments can be used, in conjunction with rapid tranquillization, under
strict guidelines and monitoring by trained staff.
2) Medication for rapid tranquillization:
• haloperidoltobeadministeredimmediately
• lorazepamfourtimesadayasrequired
Shaun has refused oral treatment; intramuscular administration is used in a non-cooperative patient
who refuses tablets.
Haloperidol is a high potency drug available for intramuscular use; it has a rapid calming and
sedative effect. The policy/good practice is to give only a single dose, although more could be
prescribed for continued agitation in the acute phase, if attempts to calm patients with
psychotherapy or a benzodiazepine (e.g. lorazepam, see Chapter 19) are unsuccessful. Haloperidol is
less sedative than some other typical antipsychotics; benzodiazepines may be used in agitated
patients if sedation is required, and are safer than antipsychotics for long-term sedation.
3) Others
• ECG(electrocardiogram—seeChapter7)
• Bloodpressure(seeChapter5)
• Admituntilstable
• Repeaturinetestweekly
For review at a multidisciplinary team meeting the following morning.
Shaun has a complex illness requiring personalized long-term treatment. Try to understand the
condition and the trail of success and failure in his treatment over the years.
1a) What is psychosis?
1b) What is schizophrenia?
2) List four positive symptoms of schizophrenia.
3) List three negative symptoms (using the clinical names) of schizophrenia experienced by Shaun.
4) What are the two factors thought to play a role in the development of schizophrenia?
Hint: Shaun’s dad had psychotic episodes.
5a) Dopamine in the brain is thought to play a central role in the pathogenesis of schizophrenia and the
action of antipsychotic drugs.
Using the figure below, a cartoon of the human brain, mark the three dopamine neuronal systems in
the brain. Indicate where the cell bodies and the major projection areas are, using in your labelling the
terms substantia nigra, striatum, ventral tegmental nuclei, corticolimbic regions, arcuate nucleus of
hypothalamus, and median eminence of hypothalamus.
WORKBOOK 15 Failure and success in long-term drug treatment 477
Top
Front Back
Cerebellum
Spinal cord
5b) For the two major projections, indicate in a single sentence the main functions they control, and a
common medical condition associated with each.
6) What came first—the treatment of schizophrenia with dopamine antagonists, or the dopamine
neurochemical theory for schizophrenia? Explain.
7a) State in a single sentence the dopamine hypothesis for schizophrenia.
7b) Explain in a single sentence the dopamine receptor theory for the therapeutic action of antipsychotic
drugs.
8a) List the five dopamine receptor types and indicate how they can be grouped into two families.
8b) Which dopamine receptor/s is/are implicated in the action of most older antipsychotics?
9a) What are the two main categories of antipsychotic drugs?
9b) Explain how the distinction is made between the two categories.
The junior nurse who has looked after Shaun at night hands over to the ward manager early the
nextday.Thejuniornursesaysthelorazepamandhaloperidolseemtobeworkingbecause
Shaun is quiet, but that during the night a further dose of intramuscular haloperidol had been
administered. They go to rouse Shaun, but find him lying in a weird posture with his eyes fixed
on the ceiling. The senior doctor administers an antimuscarinic drug, procyclidine. Shaun’s
posture rapidly returns to normal. The doctor explains that he has just suffered a type of acute
dystonic reaction (abnormal face and body movements) called an oculogyric crisis (eyes rolling
back into head), a side effect of haloperidol.
Procyclidine is an antimuscarinic drug that can be used to treat parkinsonian symptoms; it
counters the adverse effect of haloperidol on the control of movement (see Chapter 17 and
Figure 17.1).
10a) What is meant by the term ‘extrapyramidal side effects’?
10b) Name three main categories of extrapyramidal side effects.
478 Chapter 18 Schizophrenia
11a) Referring back to question 5 and the two main dopaminergic projection regions, where is
haloperidol acting to produce its beneficial therapeutic effect, and where is it acting to produce its
unwanted movement effects?
11b) Try to explain concisely why extrapyramidal side effects occur when dopamine antagonists are used.
Of all extrapyramidal symptoms, acute dystonia has the earliest onset, with most cases occurring
within a few hours to days of the beginning of treatment or an increase in dose. It is characterized
by:
• prolongedmusclecontraction
• abnormalpostures,includingtongueprotrusion
• oculogyriccrisis
• torsionoftheneck.
Past history, young age, male gender, and a high dosage of potent typical antipsychotics are all risk
factors.
12) How does procyclidine work to treat acute dystonias and other extrapyramidal side effects?
During the multidisciplinary team meeting it is agreed that an error was made by the junior doctor
in prescribing and administering further haloperidol. The pharmacist points out that intramuscular
doses of haloperidol should be lower than oral doses because of the lack of first-pass
metabolism.Theteamagreesthattheatypicalantipsychoticolanzapineshouldbetriedinstead
ofhaloperidol.LorazepamshouldbeusedasrequiredifShaunbecomesagitatedagain.
WhentheymeetwithShauntheteamapologizes,andproposesolanzapine,tellinghimthatthis
newer agent will not cause the same reaction. Shaun agrees to try it.
13) What is thought to be the mechanism of action of olanzapine which makes it different from typical
antipsychotic drugs?
14a) What are the common side effects of the atypical antipsychotics that are different from the typical
ones?
14b) Explain the theory of how these side effects are caused.
After3weeksShaunhasimprovedslightly,althoughhestillhassomesymptoms.Hispositive
symptoms have improved more than the negative ones. Despite this, he is judged safe to return
to university under the care of a community psychiatric nurse.
Six months later Shaun is back in hospital for the second time since he was discharged. Both
admissions were the result of aggressive psychotic episodes. On the first of these occasions
hisolanzapinedosewasdoubled.
During his second stay in hospital, the nurse finds Shaun’s medication under his mattress.
Shaun admits that he has not been taking the drugs because he has been putting on weight,
whichheblamesonthemedication.Thenurseagreesthatweightgainisarecognizedside
effectofolanzapine.Shaunhasdecidedthatbecausehegetsrecurrentsideeffectshewillnot
take any more medication.
WORKBOOK 15 Failure and success in long-term drug treatment 479
15) How would you counter Shaun’s argument for not taking further antipsychotic drugs?
Shaun’s concerns about side effects have led him to do some research. He asks about tardive
dyskinesia, and wants to know if he is likely to get it.
16a) What is tardive dyskinesia?
16b) Consider the drugs that have been prescribed for Shaun, and explain whether you think he is right
to be concerned about the possibility of developing tardive dyskinesia.
16c) Would it to be right to advise Shaun that there is no need for concern, because if tardive dyskinesia
occurs he would simply be taken off the drug and the problem would go away?
After 2 months Shaun seems to be having more symptoms, although they seem to be mainly
negative.Theteamdecidestoputhimonclozapine.
17a) In what way is the clinical outcome likely to be better with clozapine?
17b) Explain this with reference to the mechanism of action of clozapine.
17c) Why might clozapine not be recommended as a first-line drug?
Shaunisputontheclozapineregisterandhastohavefrequentbloodtests.
18) What is the reason for a clozapine register?
Shaunseemsstableontheclozapineandisalmostsymptomfreeayearlater.Heisnowback
with his girlfriend and will graduate at the end of the year. He asks his community psychiatric
nurse when he can stop taking the drug. He is given an appointment to see the psychiatrist who
advises him to slowly reduce and then stop the drug, if symptoms do not re-emerge.
Sometimelater,Shaunisbackontheclozapinebecausehissymptomsresurfacedwhenhe
tried to come off it. However, he now has a job and has also got married.
19a) What is the likelihood of leading a normal life after being diagnosed with schizophrenia? What
factors might influence this?
19b) Shaun asks his family doctor whether he should avoid having children, given that inheritance
contributes to the risk of developing schizophrenia. If you were the doctor what questions might you ask,
and what advice might you give?
Chapter 19
Depression and anxiety
Useful terms for this topic
Anxiety: A state characterized by arousal, vigilance,
physiological preparedness, and fear.
Bipolar depression: Mood disorder with depressive
and manic episodes.
Clinical depression: A serious medical condition in
which a person feels very sad, hopeless, unimportant,
and frequently suicidal.
Mania: Mental illness characterized by periods of
great excitement or euphoria, delusions, and
overactivity.
Monoamine hypothesis of depression: An
abnormally low level of monoamine function in the
brain leads to depressive symptoms.
Neurotrophic hypothesis of depression: Major
depression is associated with neuronal atrophy and
loss in some areas of the brain (i.e. hippocampus and
cortical regions).
Unipolar depression: Mood disorder with only
depressive episodes.
e odd thing about depression and anxiety as medical
conditions requiring treatment is that we all experience the
features of these conditions as part of the ups and downs of
our lives. Most of us feel unhappy, fed up, or sad from time to
time. It is normal to feel such things. At the extreme, though, I
may have a complete lack of interest in life, or be
overwhelmed by feelings of meaninglessness or
hopelessness, and feel so down that I fail to function in my
working and/or family life. I may even have suicidal
thoughts. If I have any combination of these symptoms for
any length of time it may be obvious to all that I need help,
that I should go and see my doctor, and that I am ill. Similarly
with anxiety—most of us worry and fret about normal things
in life, but if we are disabled or made very unhappy by worry,
rational or otherwise, then therapy (drugs or psychological)
may be justied. So, for severe forms of depression and
anxiety it is perhaps beyond dispute that medical
intervention is required. But what about milder conditions—
is it the doctor’s job to treat common unhappiness?
In both depression and anxiety the general practice doctor
and mental health specialist have to distinguish who is in
need of treatment and who is not, and, crucially, where
this need is urgent. In these conditions treatment means
psychological therapies (e.g. cognitive behavioural
therapy, or mindfulness) and/or drugs. It is clear that
psychological therapies are often desirable; they can be as
or more eective than drugs, and of course are not
accompanied by unwanted eects. However, drugs are
immediately available while rapid intervention with
psychological therapy may not be. e need for immediate
drug therapy in a minority of patients is, however,
complicated by the recognition that, as explained below,
most drugs used in this area take up to 2–3 weeks to
benet patients. For many, a combination of psychological
therapy and drugs may be the best route forward.
What if, when drugs are oered, the patient says that they
believe this is a psychological illness, not a physical one,
and so does not want to take drugs? If we are considering
milder depression and anxiety this may be a valid
viewpoint, and patient involvement in therapy may need
to explicitly recognize this. However, a patient with ‘a
psychological problem’ may well benet from drug
therapy, and indeed this may be the case for the majority
of prescriptions written for these conditions.
What follows in this chapter is an account of
antidepressant and anti-anxiety drugs (i.e. anxiolytics),
with an example of their application in a clinical situation
which is developed in Workbook 16.
Depression and anxiety often come together, and some
categories of drugs are recognized as being eective
19.1 Depression 481
against both. e ctional patient in the workbook rst
presents with anxiety, with depression developing later.
19.1 Depression
Depression is the most common mental health problem
seen in general practice. We might ask whether a
distinction can be made between depression as an illness
and depressive symptoms in an individual who is not ill.
is is explored in Table 19.1.
19.1.1 Diagnosing depression
Of course there is great uncertainty in this area, with mild
depression in particular being poorly dened. e World
Health Organization’s International Criteria for Disease
(ICD-10) has developed what is essentially a symptomcounting approach to try to recognize when depression is
a clinical condition, and to categorize dierent levels of
depression (Box 19.1).
ese issues are important to us, since they lead to
decisions about treatment and prescribing. ere are a
number of depression rating scales and patient
questionnaire approaches available to diagnose and
assess the severity of depression, some explicitly linked to
guidelines about treatment. e popularity of these varies
between dierent countries.
In general practice a screening strategy may have priority.
It may be that depression is underdiagnosed. For
instance, patients may be resistant to using the word
depression, or doctors may prefer to accept depression as
‘normal’ in old age rather than subject elderly patients to
powerful drugs. Screening here helps with the initial
identication of patients who may be clinically depressed
and in need of treatment. Depression screening
Table 19.1 Symptoms and illness in depression
Depressive symptoms Depression (illness)
13–20% of population
experience depressive
symptoms: feelings of
sadness and upset
Normal reactions to
distressing situations or
events usually pass with time
3% of population suffer
clinical depression, more than
just feeling sad or upset, and
which could include suicidal
thoughts
Intense feeling of sadness/
hopelessness/guilt; motor
retardation
Symptoms vary in severity,
duration, frequency; can have
acute onset or take years to
develop, and could be either
short-lived or chronic
Here we shall approach depression rst, before
considering issues relating to anxiety.
questionnaires may be both time- and cost-eective, with
the simplest being a two-question test: ‘During the last
few weeks have you been bothered by feeling down,
depressed, or hopeless?’ and ‘During the last few weeks
have you felt little interest or pleasure in doing things?’
19.1.2 A biological theory for depression?
Depression is probably best thought of as a psychological
illness that may have a biological basis in some or all
patients. Severe major depression may be considered a
purely ‘organic’ illness, meaning that it may be solely a
physical condition of the brain, perhaps originating from
a neurotransmitter imbalance. You may encounter
strongly held dierences of opinion on these matters.
What is clear is that changing the biological function of
the brain with drugs can profoundly alleviate symptoms
in many patients. While this doesn’t necessarily mean
that there was a biological ‘fault’ in the rst place, it does
encourage the view that a biological dierence can be
identied that contributes in some part to depressive
illness. ere are many ideas about the biological basis of
depression, but perhaps the most important for those
interested in drug action relates to the biogenic
monoamines (the monoamine neurotransmitters) of
thebrain.
e monoamine hypothesis (also called the biogenic
amine hypothesis) for depression, in its simplest form, is
that an abnormally low level of monoamine function in
the brain leads to depressive symptoms. e main
monoamines (or biogenic amines) are serotonin
(5-hydroxytryptamine; 5-HT), noradrenaline, and
dopamine (see Box 19.2, Figure b). at antidepressant
drugs interfere with the life cycle of these
neurotransmitters (see Chapter 2, Figure 2.17) in the
brain is beyond dispute. is interference may take the
form of an increase in the levels of noradrenaline/
serotonin in the synapse. Whether or not this tells us that
the problem in the rst place was an imbalance in
monoamine function is, however, in doubt. It may be wise
to conclude that we have a credible monoamine theory
for drug action, but perhaps not for depression itself.
Regardless of this, the monoamine/biogenic amine
hypothesis is important for antidepressant drug
prescribing, and so is further explored in Box 19.3.