Chapter 15

Management of Schizophrenia

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 Chapter 15: Management of Schizophrenia
1. Biological management.
2. Psychological management.
3. Social management.

1. Biological management of schizophrenia

Reference: NICE Guideline (CG178). Psychosis and schizophrenia in adults: treatment and management. Published February 2014
(last updated March 2014).

Introduction
• Choice of antipsychotic medication
o The choice of antipsychotic medication should be made by the service user and healthcare professional together, taking
into account the views of the carer if the service user agrees.
o Provide information and discuss the likely benefits and possible side effects of each drug, including:
✓ Metabolic (including weight gain and diabetes).
✓ Extrapyramidal (including akathisia, dyskinesia and dystonia).
✓ Cardiovascular (including prolonging the QT interval).
✓ Hormonal (including increasing plasma prolactin).
✓ Other (including unpleasant subjective experiences).
• How to use antipsychotic medication
o Before starting antipsychotic medication, undertake and record the following baseline investigations:
✓ Weight (plotted on a chart).
✓ Waist circumference.
✓ Pulse and blood pressure.
✓ Fasting blood glucose, glycosylated haemoglobin (HbA1c), blood lipid profile and prolactin levels.
✓ Assessment of any movement disorders.
✓ Assessment of nutritional status, diet and level of physical activity.
• Before starting antipsychotic medication, offer the person with psychosis or schizophrenia an ECG if:
o Specified in the summary of product characteristics (SPC).
o A physical examination has identified specific cardiovascular risk (such as diagnosis of high blood pressure).
o There is a personal history of cardiovascular disease or
o The service user is being admitted as an inpatient.
• Treatment with antipsychotic medication should be considered an explicit individual therapeutic trial. Include the
following:
o Discuss and record the side effects that the person is most willing to tolerate.
o Record the indications and expected benefits and risks of oral antipsychotic medication, and the expected time for a
change in symptoms and appearance of side effects.
o At the start of treatment give a dose at the lower end of the licensed range and slowly titrate upwards within the dose
range given in the British national formulary (BNF) or SPC.
o Justify and record reasons for dosages outside the range given in the BNF or SPC.
o Record the rationale for continuing, changing or stopping medication, and the effects of such changes.
o Carry out a trial of the medication at optimum dosage for 4–6 weeks.
• Monitor and record the following regularly and systematically throughout treatment, but especially during titration:
o Response to treatment, including changes in symptoms and behaviour.
o Side effects of treatment, taking into account overlap between certain side effects and clinical features of schizophrenia
(for example, the overlap between akathisia and agitation or anxiety) and impact on functioning.
o The emergence of movement disorders.
o Weight, weekly for the first six weeks, then at 12 weeks, at one year and then annually (plotted on a chart).
o Waist circumference annually (plotted on a chart).
o Pulse and blood pressure at 12 weeks, at one year and then annually.
o Fasting blood glucose, HbA1c and blood lipid levels at 12 weeks, at 1 year and then annually.
• Adherence and overall physical health.

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Treatment algorithm for schizophrenia - Reference: Maudsley Prescribing Guidelines in Psychiatry, 13th edition, 2018

Key points that patients should know - Reference: Maudsley Prescribing Guidelines in Psychiatry, 13th edition, 2018.
• Antipsychotics do not “cure” schizophrenia. They treat symptoms in the same way that insulin treats diabetes.
• Some antipsychotics may be more effective than others.
• Many antipsychotic drugs are available. Different drugs suit different patients. Perceived side effects should always be
discussed, so that the best tolerated drug can be found.
• Long-term treatment is generally required to prevent relapse.
• Antipsychotics should not be stopped suddenly.
• Psychological and psychosocial interventions increase the change of staying well.

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Efficacy
• Further to the publication of The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Study and The
Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS), the World Psychiatric Association
reviewed the evidence relating to the relative efficacy of 51 typical antipsychotics which are also known as first
generation antipsychotics (FGAs) and 11 atypical antipsychotics which are also known as second generation antipsychotics
(SGAs) and concluded that, if differences of extrapyramidal side effects (EPSEs) could be minimised (by careful dosing)
and anticholinergic use avoided, there is no convincing evidence to support the advantage for SGAs over FGAs.
• As a class, SGAs may have a lower propensity for EPSEs but this is offset by a higher propensity for metabolic side effects.
• SGAs may be superior to FGAs in treating negative symptoms. Both FGAs and SGAs treat positive symptoms.
• FGAs still play an important role in schizophrenia and offer an alternative to SGAs when SGAs are poorly tolerated or where
FGAs are preferred by the patients themselves.
• Clozapine has superior efficacy in the treatment of schizophrenia over other antipsychotics.

Types of antipsychotics
Class of agent Group Example
First generation (typical) • Phenothiazine. • Chlorpromazine.
antipsychotics • Promazine.
• Trifluoperazine.
• Fluphenazine (depot).
• Butyrophenone. • Haloperidol.
• Thioxanthene. • Flupenthixol (depot).
Note: flupenthixol has some antidepressant
effects.
• Zuclopenthixol (depot).
• Benzamide. • Sulpiride.
• Diphenylbutylpiperidine • Pimozide.
Second generation (atypical) • .
Substituted benzamide. • Amisulpride.
antipsychotics • Thienobenzodiazepine. • Olanzapine.
• Dibenzothiazepine. • Quetiapine.
• Benzizoxazole. • Risperidone.
• Paliperidone (the main active metabolite of risperidone
which itself is an atypical antipsychotic).
• Phenylindole derivative. • Sertindole.
• Dibenzodiazepine. • Clozapine.
Third generation antipsychotic • Aripiprazole.
(also an atypical antipsychotic)
Note: the threshold for antipsychotic efficacy is more than 65% D2 receptor occupancy. D2 receptor threshold applies to all
antipsychotics.
Note: the threshold for raised prolactin is more than 72% of D2 receptor occupancy.
Note: blocking more than 78% of D2 receptors produces EPSEs. This applies to both typicals and atypicals.
Note: high 5-HT2A antagonism is not protective against EPSEs.
Effects of D2 antagonism
• Mesolimbic pathway: antipsychotic efficacy is mediated by antagonism of D2 receptors in the limbic striatum.
• Mesocortical pathway: deterioration in cognitive function.
• Nigrostriatal pathway: Parkinsonism and other EPSEs.
• Tuberoinfundibular pathway: hyperprolactinaemia.

Compliance
• Poor compliance is particularly a problem with schizophrenia.
• The risk of relapse in two years for someone with schizophrenia who stops their prescribed antipsychotic medication is
approximately 75%.
• Factors associated with compliance in schizophrenia:
o Attitudes.
o Insight.
o Side effects of medications.
o The presence of negative symptoms.
o Poor psychosocial support network.
o Poor access to care.

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Benefits of antipsychotics
• Antipsychotics may be able to affect the natural course of schizophrenia.
o Repeated relapse of illness is associated with decline. Prevention of relapse by using antipsychotics may improve outcome.
o Longer duration of untreated psychosis is associated with poorer outcome.
• Antipsychotics may be neuroprotective.

Side effects of antipsychotics

• Sedation
o Greatest risk greatest with chlorpromazine (the most sedative of the phenothiazines), clozapine and olanzapine.
• Impaired glucose tolerance and diabetes
o Greatest risk with phenothiazines, clozapine and olanzapine.
o Oral glucose tolerance or fasting blood glucose should be measured before starting antipsychotic treatment and
during treatment.
• Dyslipidaemia
o Increases the risk of cardiovascular disease.
o Greatest risk is with phenothiazines, clozapine and olanzapine.
o Lipids should be measured before starting antipsychotic treatment and during treatment.
• Weight gain
o Clozapine > olanzapine > quetiapine > risperidone > amisulpride.
o Aripiprazole is weight neutral and may be associated with weight loss.
o When weight gain occurs, switching to medications with a lower risk of weight gain can be done. Alternatively,
aripiprazole can be added to existing treatment. Furthermore, dietary advice can be given.
• Metabolic syndrome
o Olanzapine is associated with the development of the metabolic syndrome (i.e. hyperinsulinaemia, low
glucose tolerance, dyslipidaemia, hypertension and obesity).
• Reduced seizure threshold
o Clozapine carries the greatest risk.
• Hypertension and QTc prolongation
o Clozapine carries the greatest risk of hypertension.
o Pimozide and sertindole carry the greatest risk of QTc prolongation.
• Postural hypotension
o Mediated through adrenergic α1 blockade.
o Increased risk when phenothiazines are prescribed for the elderly.
o Chlorpromazine, clozapine, risperidone and quetiapine all have affinity for α1 receptors, making dose titration necessary.
• Hyperprolactinaemia
o Dopamine inhibits prolactin release therefore dopamine antagonists increase prolactin levels.
o Hyperprolactinaemia produces galactorrhoea, amenorrhoea, gynaecomastia, hypogonadism, sexual dysfunction and an
increased risk of osteoporosis.
o Most plasma elevation occurs with risperidone, amisulpride and sulpiride.
o For most people with symptomatic hyperprolactinaemia, a switch to a non-prolactin elevating medication is the first choice.
An alternative is to add aripiprazole to the existing treatment.
• Anticholinergic side effects
o Dry mouth, blurred vision, constipation.
o Antipsychotics with potent anticholinergic side effects should not be given to people who have closed angle glaucoma.
• Photosensitivity
o Chlorpromazine: sunburn can be a problem.
• Peripheral oedema (e.g. ankle oedema)
o Occurs in 3% of people prescribed olanzapine.
• Sexual dysfunction
o Reported as a side effect of all antipsychotics.
o All effects are reversible.
o Antipsychotics decrease dopaminergic transmission which can decrease libido and can also increase prolactin levels
which also reduce libido.
• Neuroleptic malignant syndrome (NMS)
o A rare, but life-threatening, idiosyncratic reaction to antipsychotic medication.
o Although potent antipsychotics (e.g. haloperidol, fluphenazine) are more frequently associated with NMS, all antipsychotic
agents, typical or atypical, may precipitate the syndrome.
o Mood stabilisers (lithium, carbamazepine) and antidepressants (SSRIs, TCAs, MAOIs) have also been implicated in
NMS, as has withdrawal from antiparkinsonian agents.
o Mortality rate is up to 20%. Death usually results from respiratory failure, cardiovascular collapse, myoglobinuric
renal failure, arrhythmias or diffuse intravascular coagulation.

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o Signs/symptoms
✓ Hyperthermia (temperature above 380C).
✓ Fluctuating consciousness.
✓ Generalised rigidity (lead pipe).
✓ Autonomic instability (tachycardia, tachypnoea, fluctuating blood pressure, diaphoresis, sialorrhea).
✓ Increased creatinine phosphokinase (CPK) or urinary myoglobin level.
✓ Leukocytosis.
✓ Metabolic acidosis.
o Investigations
✓ Vital signs (pulse, blood pressure, temperature), FBC, RFT, LFT, serum CPK.
o Management
✓ Stop any agents thought to be causative (especially antipsychotics).
✓ Monitor vital signs.
✓ Benzodiazepines (e.g. lorazepam).
✓ Supportive measures such as rehydration, oxygen, correct volume depletion/hypotension with IV fluids, decrease
temperature (e.g. cooling blankets, antipyretics, cooled IV fluids, ice packs).
✓ Reverse dopamine blockade: bromocriptine (a dopamine agonist).
✓ Reduce rigidity: dantrolene (a muscle relaxant).
✓ If rhabdomyolysis occurs: hydration and alkalinisation of the urine using IV sodium bicarbonate to prevent renal
failure.
o Restarting antipsychotics
✓ Stop antipsychotics for at least five days.
✓ Begin with a small dose and increase gradually while monitoring vital signs and CPK.
✓ Consider using a different antipsychotic (e.g. quetiapine or clozapine).

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 • Extrapyramidal side effects (EPSEs)
Dystonia Parkinsonism/ Akathisia Tardive dyskinesia
pseudoparkinsonism
Signs and • Sustained involuntary • Tremor. • A movement • Repetitive, involuntary,
symptoms muscular spasms which are • Rigidity. disorder characterised by a purposeless movements:
often painful: • Bradykinesia. feeling of unpleasant inner o Grimacing.
o Cervical dystonia restlessness and a o Tongue protrusion.
(torticollis): neck twists and compelling need to be in o Lip smacking.
turns to one side. In addition, constant motion, e.g. o Puckering and
the head may be pulled pursing of the lips.
o Rocking while
forward or backward.
standing or sitting. o Rapid eye blinking.
o Opisthotonus: arching of
o Lifting the feet as if o Rapid movements of
the back.
o Blepharospasm: marching on the spot. the extremities may also
involuntary, forcible closure of o Crossing and occur (upper extremities
the eyelids. uncrossing the legs while affected > lower
o Oculogyric crisis: upward sitting. extremities).
deviation of the eyes. • People with akathisia
are unable to sit or keep
still, describe restlessness,
fidget, rock from foot to
foot and pace.
Prevalence • Approximately 10%. • Approximately • Approximately 25%. • Approximately 5%.
• More common in: 20%. • More common in:
o Young males. • More common in: o Elderly females.
o Neuroleptic naïve. o Elderly o Presence of
o Use of high potency females. organic brain illness,
drugs e.g. haloperidol). o Those with pre- alcohol dependency,
existing affective illness,
neurological
damage (head diabetes and
injury, stroke, intellectual
etc). disability.
o Those who had
acute EPSE early
in treatment.
o Concomitant
anticholinergic
treatment
Treatment Anticholinergics (e.g. • Dose reduction. • Reduce antipsychotic dose. • Stop anticholinergics.
options procyclidine, biperiden). • Change to an • Change to an atypical. • Decrease
atypical antipsychotic. • Propranolol, or antipsychotic dose.
• Anticholinergics (e.g. clonazepam, or Note: dose reduction may
procyclidine, cyproheptadine initially worsen tardive
(antihistamine), or
biperiden). dyskinesia.
mirtazapine, or trazodone,
or mianserin, or clonidine. • Change to an
Note: anticholinergics are atypical.
generally unhelpful. • Clozapine.
Note: a family history of a primary movement disorder (Parkinson’s disease, dystonia, tremor) is a risk factor for EPSEs.
Note: tardive dyskinesia can occur in people with psychosis who have never taken antipsychotics.
Are antipsychotics good or bad for your health?
• Two large studies examined the population of Finland.
• People with schizophrenia on antipsychotics lived longer than those not on antipsychotics.
• The longer on antipsychotics, the more benefit people received.
• People on clozapine lived longest of all.
• In schizophrenia, antipsychotics at low and moderate dose protect against cardiovascular mortality, and at higher doses all-cause
mortality is reduced by 25% (lower suicide rates).
• Therefore, antipsychotics done well, in collaboration with the patient, for part of a mortality reduction plan.

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 Clozapine
Introduction
• Patients on clozapine must be registered with an approved monitoring system (e.g. Clozapine Patient Monitoring Service
[CPMS]). Each patient prescribed clozapine receives a unique, identifying number (e.g. CPMS number).
• Initiation of clozapine is done as an inpatient or where appropriate facilities exist for monitoring (e.g. at a day hospital).
• A normal leukocyte count (WBC > 3,500/mm3, neutrophils > 2,000/mm3) must precede treatment initiation.
• FBCs must be repeated (and results sent to CPMS) at weekly intervals for 18 weeks (when the risk of
neutropenia/agranulocytosis is greatest) and then fortnightly until one year. Blood monitoring continues monthly after one year
of treatment.
• Dose of clozapine should be titrated up slowly. Need for close monitoring of vital signs on initiation because of
hypotensive effect.
• If the patient has not received clozapine for 48 hours or longer, restart clozapine at the starting dose and re-titrate upwards.
• Response to clozapine occurs in 30-60% of people with treatment resistant schizophrenia.
• 40-70% of people with treatment resistant schizophrenia are also clozapine resistant.
• Clozapine reduces suicidality, hostility, aggression and both positive and negative symptoms.
• Clozapine does not increase prolactin release in humans.

Indications
• Treatment resistant schizophrenia (main indication).
• Tardive dyskinesia.
• Psychosis in Parkinson’s disease.
• Huntington’s psychosis.
• Resistant mania.

Reference: NICE Guideline (CG178). Psychosis and schizophrenia in adults: treatment and management. Published February
2014 (last updated March 2014).
• For people with schizophrenia whose illness has not responded adequately to pharmacological or psychological treatment:
o Review the diagnosis.
o Establish that there has been adherence to antipsychotic medication, prescribed at an adequate dose and for the correct
duration.
o Review engagement with and use of psychological treatments and ensure that these have been offered according to this
guideline. If family intervention has been undertaken suggest CBT; if CBT has been undertaken suggest family
intervention for people in close contact with their families.
o Consider other causes of non-response, such as co-morbid substance misuse (including alcohol), the concurrent use
of other prescribed medication or physical illness.
• Offer clozapine to people with schizophrenia whose illness has not responded adequately to treatment despite the
sequential use of adequate doses of at least two different antipsychotic drugs. At least one of the drugs should be a non-clozapine
second-generation antipsychotic.
• For people with schizophrenia whose illness has not responded adequately to clozapine at an optimised dose, healthcare
professionals should consider the first black bullet point in this section entitled “reference: NICE Guideline (CG178)”
(including measuring therapeutic drug levels) before adding a second antipsychotic to augment treatment with clozapine.
An adequate trial of such an augmentation may need to be up to 8-10 weeks. Choose a drug that does not compound the
common side effects of clozapine.

Baseline investigations (before commencing clozapine)

• Bloods (FBC, fasting cholesterol, lipids and glucose level), ECG, chest X ray, weight.
• Physical examination.
• Vital signs (blood pressure, pulse, temperature, respiratory rate).

Plasma level measurements

• Plasma levels of clozapine, norclozapine and the clozapine to norclozapine ratio can be measured after three weeks of starting
clozapine and at intervals during treatment.
o Norclozapine is the active metabolite of clozapine.
o Norclozapine has a longer half-life than clozapine.
o Mean clozapine to norclozapine ratio is 1.33 across dose ranges.
✓ > 3 suggests the sample was not at the ‘trough’ stage.
✓ < 0.5 suggests poor compliance.
• Clozapine plasma levels are reduced in: males, younger patients, smokers.
• Clozapine plasma levels are increased in: Asians.
• In those not responding to clozapine, the dose should be adjusted to give a clozapine plasma level in the range 350-500ug/l.
Those not tolerating clozapine may benefit from a reduction to a dose giving a plasma level within this range.

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Sites of action
• Dopamine receptors
o Low affinity for D2 receptors compared to typical antipsychotics.
o Affinity for D4 receptors is approximately 10 times greater than for D2 receptors.
o Also binds to D1, D3 and D5 receptors.
• Serotonin receptors: affinity for 5-HT receptors.
• Adrenergic receptors: affinity for α1 and α2 receptors.
• Muscarinic receptors.

Main side effects

Side effect Management
Agranulocytosis (incidence 0.8%) or • Stop clozapine, admit to hospital.
neutropenia (incidence 3%).
Note: agranulocytosis:
• Females > males.
• Older individuals > younger
individuals.
• Asians > Caucasians.
Sedation. • Reduce the morning dose.
Weight gain. • Diet, exercise.
Constipation. • High fibre diet, laxatives.
Hypersalivation. • Hyoscine hydrobromide (‘Kwells’), carry a cloth to absorb the saliva, use an extra
pillow at night.
Hypotension. • Stand up slowly, reduce the dose, slow down the rate of increase.
Hypertension. • Reduce the dose, slow down the rate of increase, medication (e.g. atenolol) may
be needed.
Tachycardia. • Reduce the dose, slow down the rate of increase.
Nausea. • Anti-emetic.
Fever. • Anti-pyretic, check FBC.
Seizures. • After a seizure, withhold clozapine for one day, re-start at a reduced dose and
give sodium valproate.
Exacerbates OCD symptoms. • Addition of an SSRI.

Additional side effects

• Haematological: eosinophilia, thrombocytopenia.
• Nervous system: dizziness/vertigo, headache, tremor, syncope, delirium.
• Cardiovascular: myocarditis, cardiomyopathy.
• Gastrointestinal: transient moderate asymptomatic elevations in liver function tests, pancreatitis.
• Genitourinary: urinary incontinence/nocturnal enuresis, urinary urgency/frequency, urinary retention.
• Endocrine: increased risk of developing hyperglycemia and/or diabetes mellitus.
• Respiratory: pneumonia.

Clozapine augmentation
• Clozapine augmentation can be used in cases of inadequate response to clozapine.
• Suggested options for augmenting clozapine: add haloperidol or amisulpride or sulpiride or risperidone or aripiprazole
or omega-3 triglycerides.
Antipsychotic depot injections
Introduction
• Antipsychotics can be given as a long-acting depot injection injected into a large muscle (usually the gluteus maximus),
allowing for sustained release over one to four weeks.
• Depot injections reduce relapse rates of schizophrenia.

Indications
• Poor compliance with oral treatment.
• Failure to respond to oral medication.
• Memory problems or other factors interfering with the ability to take medication regularly.

Specific side effects

• Pain/swelling at the injection site, rarely abscess, nerve palsies.
• Side effects as for oral medication may take two to three days to emerge and may persist for weeks after discontinuation.

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 2. Psychological management of schizophrenia
Reference: NICE Guideline (CG178). Psychosis and schizophrenia in adults: treatment and management. Published February 2014
(last updated March 2014).
• CBT should be delivered on a one-to-one basis over at least 16 planned sessions and
o Follow a treatment manual so that:
✓ People can establish links between their thoughts, feelings or actions and their current or past symptoms, and/or
functioning.
✓ The re-evaluation of people's perceptions, beliefs or reasoning relates to the target symptoms.
o Also include at least one of the following components:
✓ People monitoring their own thoughts, feelings or behaviours with respect to their symptoms or recurrence of
symptoms.
✓ Promoting alternative ways of coping with the target symptom.
✓ Reducing distress.
✓ Improve functioning.
• Family intervention should:
o Include the person with psychosis or schizophrenia if practical.
o Be carried out for between three months and one year.
o Include at least ten planned sessions.
o Take account of the whole family's preference for either single-family intervention or multi-family group intervention.
o Take account of the relationship between the main carer and the person with psychosis or schizophrenia.
o Have a specific supportive, educational or treatment function and include negotiated problem solving or crisis
management work.
• Offer CBT to all people with psychosis or schizophrenia. This can be started either during the acute phase or later,
including in inpatient settings.
• Offer family intervention to all families of people with psychosis or schizophrenia who live with or are in close contact with
the service user). This can be started either during the acute phase or later, including in inpatient settings.
• Consider offering arts therapies to all people with psychosis or schizophrenia, particularly for the alleviation of negative
symptoms. This can be started either during the acute phase or later, including in inpatient settings. Aims of arts therapies
should include:
o Enabling people with psychosis or schizophrenia to experience themselves differently and to develop new ways of
relating to others.
o Helping people to express themselves and to organise their experience into a satisfying aesthetic form.
o Helping people to accept and understand feelings that may have emerged during the creative process (including, in some
cases, how they came to have these feelings) at a pace suited to the person.
• When psychological treatments, including arts therapies, are started in the acute phase (including in inpatient settings), the
full course should be continued after discharge without unnecessary interruption.
• Do not routinely offer counselling and supportive psychotherapy (as specific interventions) to people with psychosis or
schizophrenia. However, take service user preferences into account, especially if other more efficacious psychological
treatments, such as CBT, family intervention and arts therapies, are not available locally.
• Do not offer adherence therapy (as a specific intervention) to people with psychosis or schizophrenia.
• Do not routinely offer social skills training (as a specific intervention) to people with psychosis or schizophrenia.

For people with schizophrenia whose illness has not responded adequately to biological or psychological management
• Review the diagnosis.
• Establish that there has been adherence to antipsychotic medication, prescribed at an adequate dose and for the correct duration
(i.e. compliance?).
• Review engagement with and use of psychological treatments.
o If family intervention has been undertaken, suggest CBT. If CBT has been undertaken, suggest family intervention
for people in close contact with their families
• Consider other causes of non-response, such as co-morbid substance misuse (including alcohol), the concurrent use of other
prescribed medication or physical illness.

3. Social management of schizophrenia

• See Chapter 8.

Note: the biological, psychological and social management strategies given in Chapter 8 are general options without considering
any particular patient. However, it is important to tailor the management strategies to each individual patient by selecting those
options which are appropriate for that case.

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Notes – Chapter 15

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