TREATMENT STRATEGY AND PSYCHOPHARMACOLOGY
Antipsychotics
Kalliopi Vallianatou
Abstract
First generation (typical) and second generation (atypical) antipsychotics
are the mainstay of psychosis treatment. Most antipsychotics block dopa-
mine D2 receptors. Greater affinity for serotonin 5-HT2 receptors over D2
and fast dissociation from the D2 receptor are the two competing theories
for the activity of atypical antipsychotics. Movement disorders, hyperpro-
lactinaemia, cardiac and metabolic disorders are common antipsychotic
adverse effects. Antipsychotic long-acting injections are also available
in addition to oral formulations.
Keywords antipsychotic; dopamine; psychosis; serotonin
Antipsychotic drugs reduce the severity of psychotic symptoms
and prevent relapse in schizophrenia1 and other psychotic
disorders (see Medicine 2012; 40(11): 586e590). They are also
used in mania, depression and delirium, amongst other condi-
tions. There are two classes: older typical or conventional or first
generation antipsychotics (FGAs); and newer atypical or second
generation antipsychotics (SGAs).
Basic principles of prescribing antipsychotics for psychotic
disorders2e4
 For first-episode schizophrenia, offer an oral antipsychotic
at the lowest recommended therapeutic dosage. Agree the
choice with the patient.
 Increase the dosage after 2 weeks if the response is poor.
 Aim for the lowest effective dosage, as many adverse
effects are dose-related.
 Prescribing as required antipsychotics for a calming effect
increases the risk of the patient exceeding the maximum dose,
resulting in a greater burden of adverse effects including
oversedation or cardiac disorders and greater risk of drug
interactions.
 Antipsychotic combinations should be avoided, apart from
during short periods of switching between two antipsy-
chotics, and considered only in consultation with
a psychiatrist due to increased risk of QTc prolongation.
 Continue treatment with the antipsychotic for at least 1e2
years, or longer for patients with multiple episodes.
First generation antipsychotics (FGAs)
FGAs are those associated with acute extrapyramidal symptoms
(EPS) even at therapeutic dosages.1,5 FGAs share some class-
specific adverse effects but differ in both chemical structure
and receptor binding.5 Commonly prescribed FGAs in the UK
Kalliopi Vallianatou MPharm Senior Clinical Pharmacist, South London
and the Maudsley NHS Foundation Trust, Maudsley Hospital, London,
UK. Conflicts of interest: none declared.
MEDICINE 40:12
include chlorpromazine, trifluoperazine, haloperidol,
pentixol, zuclopenthixol, pipotiazine and fluphenazine.
flu-
Second generation antipsychotics (SGAs)
SGAs are characterized by lower incidence of EPS and, with some
exceptions (amisulpride, risperidone), a lack of sustained increase
in plasma prolactin concentration (hyperprolactinaemia).6 The
defining feature of atypicality for this group of drugs has not been
concluded. Commonly prescribed SGAs in the UK include risper-
idone, olanzapine, quetiapine, aripiprazole, amisulpride, sulpir-
ide, clozapine, paliperidone and asenapine.
Mode of action
Most antipsychotics act as antagonists at D2 receptors in the mes-
olimbic pathway (to reduce positive symptoms) or in the meso-
cortical pathway (to reduce negative symptoms), but D2 receptor
blockade in the striatum (causing extrapyramidal symptoms) and
tuberoinfundibular pathway (causing hyperprolactinaemia) can
also occur.1 D2 occupancy for antipsychotic effect may lie within
65%e70%, whereas above 72% adverse effects may emerge.7
Some antipsychotics also block serotonergic 5-HT2, a1-adre-
noceptors, H1-histamine and muscarinic receptors.5 Some SGAs
show lower affinity for D2 receptors, which is thought to account
for decreased EPS and improvement in affective and cognitive
effects.6 Unlike most other antipsychotics, aripiprazole is
a partial D2 and 5-HT1a agonist. Aripiprazole binds to D2 recep-
tors and both blocks and stimulates them.8
Efficacy
Olanzapine, risperidone and amisulpride may be modestly more
efficacious than FGAs.3,4 Olanzapine is second only to clozapine
in its efficacy.9 About 30% of schizophrenia patients will be
treatment resistant3 and more than half of these may respond to
clozapine. Antipsychotic depots or long-acting injections (LAIs)
also exist and are commonly prescribed where adherence to oral
medication is problematic.10
Clozapine is indicated for use after the failure of two prior
antipsychotics, including an SGA. It is associated with an
increased risk of potentially fatal neutropenia or agranulocytosis
and thus regular haematological monitoring is required. Trough
clozapine plasma concentration should be checked following
completion of dose titration, 2e3 days after any dose change or
following a change in smoking habit (target 0.35e0.5 mg/litre). If
concentrations over 0.5 mg/litre are found then seizure prophy-
laxis with sodium valproate or lamotrigine should be considered.4
Adverse effects
Antipsychotics are associated with a wide range of adverse
effects, such as movement disorders, hyperprolactinaemia,
postural hypotension, prolongation of the QTc interval and the
metabolic syndrome (Table 1). The last of these comprises
obesity, dyslipidaemia, diabetes and hypertension and has been
a concern with the use of SGAs.11 Consequently, baseline tests
should be carried out before an antipsychotic is prescribed and
after treatment has started. Tests include full blood count, renal
function, lipids, plasma glucose, liver function tests, creatine
kinase, prolactin, ECG, blood pressure, pulse and weight.4 Full
676 2012 Elsevier Ltd. All rights reserved.
 TREATMENT STRATEGY AND PSYCHOPHARMACOLOGY

Adverse effects of antipsychotics4,11

Adverse effect Antipsychotics

Extrapyramidal symptoms4,11
Dystoniaa Muscle spasm (e.g. eyes rolling, More common with FGAs. Incidence is higher with haloperidol,
head and neck) fluphenazine, trifluoperazine, perphenazine. Dystonias are reported
for several SGAs but incidence is low.
Pseudo-parkinsonism Resting tremor, rigidity, bradykinesia, Incidence rates as for dystonia.
masked faces
Akathisiab Restlessness, nervousness, compulsion Rates of akathisia are about 25% less for SGAs than FGAs. More likely
to keep moving with aripiprazole than other SGAs.
Tardive dyskinesiac Lip-smacking, pill rolling More common in the elderly and in those with acute EPS at start of
treatment. Risk is higher with FGAs than SGAs.4,11
Cardiac
Postural hypotension Drop in blood pressure on standing, light Common with clozapine, risperidone, quetiapine.4
headedness, blurred vision
QTc prolongation (QTc normal limits are: men <440 ms, Is usually plasma drug concentration-dependent. Common with
women <470 ms) haloperidol. Moderate effect with amisulpride, quetiapine,
chlorpromazine.
Tachycardia Rapid heart rate (often >100 bpm) Common with clozapine.
Other
Metabolic Weight gain, waist circumference >35 Risk is highest with clozapine and olanzapine. Moderate with quetiapine
inches for women or >40 inches for men, and risperidone. Low with high-potency FGAs, aripiprazole and
dyslipidaemia, diabetes amisulpride.4
Hyperprolactinaemia Galactorrhoea, gynaecomastia, amenorrhoea, Common with FGAs and some SGAs including risperidone, paliperidone
loss of libido, sexual dysfunction, reduction and amisulpride.4 Not seen with aripiprazole (which lowers plasma
in bone mineral density prolactin concentration), clozapine and quetiapine.
Anticholinergic Dry mouth, urinary retention, constipation More common with some FGAs and clozapine.
and sedation
a
For treatment anticholinergic drugs are given (PO/IM/IV depending on severity).
b
Not responsive to anticholinergics. Dose reduction, b-blockers or benzodiazepines may help.
c
Switch to an SGA; stop any anticholinergics as they may worsen tardive dyskinesia.

Table 1

blood counts are required for clozapine treatment, which follow
a strict monitoring protocol.
A rare, potentially fatal, reaction to antipsychotics is the
neuroleptic malignant syndrome (NMS), which presents with
fever, rigidity, confusion, autonomic instability, tachycardia,
abnormal blood pressure, elevated creatine kinase (CK), leuco-
cytosis and altered liver function tests.4 NMS constitutes a medical
emergency and patients may require intensive care treatment.4
Drug interactions12,13
 Clozapine: plasma levels are increased by paroxetine, cit-
alopram, ciprofloxacin, erythromycin, caffeine and ritonavir
and decreased by smoking and carbamazepine. Concomi-
tant use of clozapine with carbamazepine should be avoi-
ded due to increased risk of bone marrow suppression.12
 Increased risk of ventricular arrhythmias when antipsy-
chotics that prolong QTc are given with amiodarone.
 Increased risk of bradycardia and respiratory depression
when intramuscular (IM) olanzapine is given with IM
benzodiazepines.
 Antipsychotics antagonize the anticonvulsant effect of
antiepileptics (by lowering the seizure threshold).
 Plasma levels of quetiapine, olanzapine, risperidone and
aripiprazole are reduced by carbamazepine.
A
Antipsychotics in vulnerable groups
Pregnancy3,4
C In unplanned pregnancy reassure the patient and discuss the
risks of stopping or switching medication or leaving the
condition untreated.
C Patients on antipsychotics considering future pregnancy
should be informed that hyperprolactinaemia may reduce the
chances of pregnancy.
C Most data are for low-dose FGAs (e.g. chlorpromazine, halo-
peridol, trifluoperazine).
C If the patient is taking clozapine or olanzapine, monitor for
gestational diabetes.
C Use the lowest effective dose. The activity of some drug-
metabolizing enzymes may be changed leading to higher or
lower plasma drug concentration.
C Avoid long-acting injections and anticholinergic drugs.

MEDICINE 40:12 677 2012 Elsevier Ltd. All rights reserved.

 TREATMENT STRATEGY AND PSYCHOPHARMACOLOGY
Hepatic impairment4
C Start with low doses and increase slowly, increase dose
interval, monitor LFTs weekly.
C Sulpiride and amisulpride e no dose adjustment required if
normal renal function.
C Avoid chlorpromazine (hepatotoxic) and long-acting injections
C Haloperidol may be preferred although it has a caution in liver
disease.
Renal impairment4,14
C Start with small doses as increased CNS sensitivity and EPS in
renal impairment.
C Avoid long-acting injections and QTc-prolonging drugs.
C Avoid sulpiride and amisulpride as they are primarily renally
excreted.
C Haloperidol (e.g. 2e6 mg/day) or olanzapine (5 mg/day) may
be suggested.
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678 2012 Elsevier Ltd. All rights reserved.