British Medical Bulletin, 2015, 114:169–179

doi: 10.1093/bmb/ldv017
Advance Access Publication Date: 8 May 2015

Antipsychotic medication in schizophrenia:

a review
John Lally†,* and James H. MacCabe‡
†
Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s
College London, London, United Kingdom, and ‡National Psychosis Service, South London and Maudsley
NHS Foundation Trust, London, United Kingdom
*Correspondence address. Department of Psychosis Studies, PO63, Institute of Psychiatry, Psychology & Neuroscience
(IoPPN), King’s College London, De Crespigny Park, London SE5 8AF. Tel: +(0044) (0)20 7848 0216; Fax: +(0044) 020 7848 0287;
E-mail john.lally@kcl.ac.uk
Accepted 1 April 2015

Abstract
Introduction: Antipsychotic medications are mainstays in the treatment of
schizophrenia and a range of other psychotic disorders.
Sources of data: Recent meta-analyses of antipsychotic efficacy and toler-
ability have been included in this review, along with key papers on anti-
psychotic use in schizophrenia and other psychotic illnesses.
Areas of agreement: The heterogeneity in terms of individuals’ response to
antipsychotic treatment and the current inability to predict response leads to
a trial-and-error strategy with treatment choice. Clozapine is the only effect-
ive medication for treatment-resistant schizophrenia.
Areas of controversy: There are a significant number of side effects asso-
ciated with antipsychotic use. With a reduction in the frequency of extrapyr-
amidal side effects with the use of second-generation antipsychotics, there
has been a significant shift in the side effect burden, with an increase in the
risk of cardiometabolic dysfunction.
Growing points: There exist small and robust efficacy differences between
medications (other than clozapine), and response and tolerability to each
antipsychotic drug vary, with there being no first-line antipsychotic drug that
is suitable for all patients.
Areas timely for developing research: A focus on the different symptom
domains of schizophrenia may lead to endophenotypic markers being identi-
fied, e.g. for negative symptoms and cognitive deficits (as well as for positive
symptoms) that can promote the development of novel therapeutics, which

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 170 J. Lally et al., 2015, Vol. 114

will rationally target cellular and molecular targets, rather than just the dopa-
mine 2 receptor. Future developments will target additional processes,
including glutamatergic, cholinergic and cannabinoid receptor targets and
will utilize personalized medicine techniques, such as pharmacogenetic var-
iants and biomarkers allowing for a tailored and safer use of antipsychotics.
Key words: schizophrenia, antipsychotic medication, psychotic disorders

Introduction with excess dopaminergic activity in the mesolimbic

Antipsychotic medications are primarily indicated for
the treatment of schizophrenia and other psychotic
disorders [including schizoaffective disorder, delu-
sional disorder and bipolar affective disorder (BPAD)].
They have traditionally been categorized as first-gener-
ation (formerly known as ‘typical’ or ‘conventional’)
antipsychotics (FGAs) or second-generation antipsy-
chotics (SGAs) (formerly ‘atypical’ antipsychotics).
The burden of side effects associated with FGAs,
in particular debilitating extrapyramidal side effects
(EPSEs), led to the introduction of the SGA medica-
tions in the 1990s. The SGAs have a lower propensity
to cause EPSEs (i.e. acute dystonias, akathisia, parkin-
sonism and tardive dyskinesia) compared with the
FGAs, and these properties, aligned with their differen-
tiating receptor profiles, led them to be labelled as
‘atypical’.1 The 8 SGAs that are currently licensed for
use in the UK (12 in total are licensed in Europe) were
modelled on the pharmacological profile of clozapine,
due to its low propensity to cause EPSEs and superior
effectiveness in refractory schizophrenia.2 The SGAs
are associated with a lesser burden of EPSEs at moder-
ate doses (though they are not free from inducing
EPSEs, with some such as aripiprazole carrying a
risk of akathisia of ∼10%), but many are associated
with increased risk of cardiometabolic abnormalities,
including weight gain, dyslipidaemia and glucose
dysregulation.
Mechanism of antipsychotic action
D2 receptor antagonism in the brain is a general
pharmacodynamic property of all antipsychotics;
this has given rise to the hypothesis that schizophre-
nia involves a dysregulation of dopaminergic circuits
pathway (leading to positive symptoms of psychosis)
and reduced dopaminergic signalling in the mesocor-
tical pathway (leading to negative symptoms). Evi-
dence for the dopamine hypothesis comes from not
only the efficacy of D2 receptor antagonists, but also
through the effects of D2 agonists such as amphet-
amine in precipitating psychosis and the effects of
dopamine-depleting drugs such as reserpine in redu-
cing psychotic symptoms.3
Antipsychotic action has consistently been shown
to occur when the occupation of striatal D2 recep-
tors is more than 65%, but further increases in the
level of D2 blockade are not associated with improved
antipsychotic efficacy; rather, it leads to the onset of
side effects such as EPSEs and hyperprolactinaemia.
A threshold dose for EPSEs occurs when ∼80% of the
D2 receptors are occupied and for hyperprolactinae-
mia when D2 blockade exceeds 72%.4 Despite the
association of striatal dopamine blockade with the
risk of EPSEs, it is important to note that this is not
the critical site of action for therapeutic effect, which
occurs most prominently in the mesolimbic brain
system.
Clozapine: a special case
Clozapine is unique among antipsychotic medica-
tions and can be viewed as a standalone ‘third class’
of antipsychotic. It is the only antipsychotic medica-
tion that has proven effectiveness in treatment-resist-
ant schizophrenia (TRS). The precise mechanism of
clozapine’s superior effectiveness in TRS has not
been established, but some 50–60% of patients with
schizophrenia refractory to other antipsychotics will
respond to clozapine.5 Clozapine produces robust
antipsychotic effect at <65% threshold of striatal D2

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 Antipsychotic medication in schizophrenia, 2015, Vol. 114
receptor blockade,4 suggesting that beyond D2
receptor blockade in the striatum, other receptors or
mechanisms also contribute to its therapeutic effect.
Clozapine and TRS are considered in greater
detail in the following text.
Clinical efficacy of FGA versus SGA
The introduction of SGAs was thought to be a revolu-
tion in the treatment of schizophrenia. Initially, claims
were made that the SGAs had better efficacy for
positive and negative symptomatology and cognitive
deficits as well as improved tolerability. However, over
time, this initial enthusiasm and optimism for thera-
peutic advantages for the SGAs as a class have
diminished.
The Clinical Antipsychotic Trials of Intervention
Effectiveness (CATIE)6 and the Cost Utility of the
Latest Antipsychotic Drugs in Schizophrenia Study
(CUtLASS),7 which compared FGAs and SGAs,
failed to show a difference between FGAs and SGAs
in rates of treatment discontinuation, improvement
in psychotic symptoms or quality of life.6,7 CATIE
further failed to demonstrate that SGAs were more
effective in the reduction of negative or cognitive
symptoms than FGAs. The results of CATIE and
CUtLASS demonstrated similarities in treatment
response, though with SGAs carrying a lower risk of
tardive dyskinesia. Further evidence for clozapine’s
unique position among antipsychotics was provided,
with it found to be superior to other SGAs in both
CATIE and CUtLASS.
In 2012, a multi-treatment meta-analysis asses-
sing the efficacy of antipsychotic medication in ran-
domized controlled trials (RCTs) in patients with
schizophrenia demonstrated that all antipsychotic
medications were significantly more effective than
placebo. This showed that antipsychotics had a relapse
rate of 28% compared with a relapse rate of 64% for
placebo over a 7–12-month follow-up period.8 The
effect size is comparable with that seen for many treat-
ments for non-psychiatric disorders, such as hyperten-
sion, hypercholesterolaemia and type 2 diabetes.9 This
indicates that antipsychotic medications are not less
effective when prescribed for their target conditions,
than those used by other medical specialties.
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171
In a more recent meta-analysis, the separation of
antipsychotic medications into FGA and SGA group-
ings has been further called into question, with
similar efficacy between the groups seen.10 The most
efficacious antipsychotics in this meta-analysis were
the SGAs that were first developed, with small but
robust differences seen in efficacy for amisulpride,
olanzapine and risperidone (and for clozapine, but
the effect for clozapine was diminished by the exclu-
sion of studies with TRS patients).
Antipsychotic medication and adverse
effects
In Leuchts’ meta-analysis,10 amisulpride proved to
be the best in terms of tolerability, with less discon-
tinuation due to side effects compared with placebo.
Haloperidol was the worst drug for discontinuation
rates compared with placebo. Haloperidol was iden-
tified as the medication most likely to cause EPSEs,
while weight gain and metabolic dysfunction were
most notably identified with the use of olanzapine
and clozapine (and to a lesser extent with risperidone
and quetiapine),10 findings that have been consist-
ently replicated in other studies.11
Cardiometabolic adverse effects
Higher rates of modifiable cardiovascular risk factors
are seen in schizophrenia, with 33% of patients with
schizophrenia meeting the criteria for metabolic
syndrome throughout the course of the illness.12 The
increased risk for cardiometabolic risk factors is
multifactorial with genetic factors and the cumulative
long-term effect of poor health behaviours and long-
term exposure to antipsychotic drug postulated as
causes.
SGAs are associated with higher rates of meta-
bolic dysfunction compared with FGAs (though
FGAs such as chlorpromazine are associated with
increased cardiometabolic risk and it remains the
case that the cardiometabolic risk associated with FGAs
has not been as extensively studied as with SGAs).
Clozapine and olanzapine both have the greatest
affinity for 5-HT2C and Histamine (H) 1 receptors
and the greatest weight gain potential, which can
 172
occur early in the course of treatment,13 before plat-
eauing as the treatment continues.11 The most dra-
matic weight gain is seen in antipsychotic naïve
patients over the first 6 weeks of treatment and for
the majority, those with initial weight gain did not
lose that weight thereafter, even after switching to
more weight-neutral antipsychotics.14 SGAs such as
aripiprazole, lurasidone and asenapine have a more
neutral metabolic side effect profile.
Physical health monitoring
It is recommended that all patients while treated with
antipsychotics are monitored regularly for cardiome-
tabolic risk factors. Despite this, and the cumulative
cardiometabolic risk factors, monitoring of physical
health parameters in those treated with schizophre-
nia continues to be poor.15 For an individual starting
an antipsychotic for the first time (and for any future
antipsychotic changes), the following are recom-
mended to be monitored: weight, at baseline, then
weekly for the first 6 weeks, then at 12 weeks, at
1 year, and then annually ( plotted on a chart) (more
frequently at the start of treatment as rapid early
weight gain may predict severe weight gain in the
longer term14); waist circumference at baseline and
then annually ( plotted on a chart) (waist size or BMI
have been suggested as a simple screening test for
metabolic syndrome in schizophrenia12); and blood
pressure, fasting blood glucose, HbA1c, and blood
lipid and serum prolactin levels at baseline, at 12
weeks, at 1 year, and then at least annually.16
Further, pharmacological and non-pharmacological
interventions for weight loss and cardiometabolic dys-
function should be initiated when required.
Choice of antipsychotic
At present, there are no specific biomarkers or phar-
macogenetic tests to guide the choice of treatment.
According to the National institute for health and
care excellence guidelines, a person presenting with a
first episode of schizophrenia or a first episode of
psychosis (FEP) should be offered treatment with an
antipsychotic. The onset of the response to treatment
is highly variable, but meta-analysis has indicated that
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J. Lally et al., 2015, Vol. 114
the largest part of antipsychotic medication effect
takes place within the first week (excluding the use of
clozapine), and thereafter the improvements are more
marginal.17
If a patient does not have a response to anti-
psychotic treatment at 4–6 weeks, then the recom-
mendation is to switch to an antipsychotic medication
with a different receptor-binding profile.18 It is impor-
tant to ensure that the patient is adherent to treatment
and that it is not a case of medication intolerability
that has led to a poor response. Antipsychotic medica-
tions should be titrated to a therapeutic dose (e.g.
olanzapine 5–10 mg daily or risperidone 2–4 mg
daily in the first episode of schizophrenia) in order to
assess treatment response. It is only a small propor-
tion of patients with an FEP (∼15–20%) that will not
have a further episode of psychosis, but at this stage
of the illness, it is not possible to predict who will not
relapse once maintenance treatment is discontinued.
How long to continue?
Maintenance treatment is recommended for all, with
first-episode patients treated for at least 1 year, while
those with multi-episodes should have treatment for
at least 5 years. Further, the severity of the acute
episode, namely the degree of symptomatology that
somebody presents with and the risk of violence and
suicidality, which may be associated with the acute
episode, will increase the likelihood that longer-term
maintenance treatment be recommended. The dis-
continuation of antipsychotic medication has been
shown to be associated with a fivefold increased risk
of relapse over a 5-year follow-up period compared
with maintenance therapy.19 It is standard practice
to continue the medication that was effective in the
acute phase as long as it is well tolerated.
Switching antipsychotics
There are different methods for switching anti-
psychotic medications, if required for clinical inef-
fectiveness or intolerability. This may involve a
crossover where one medication is gradually tapered
while the second medication is concurrently titrated
to its full dose. Another approach is to abruptly stop
 Antipsychotic medication in schizophrenia, 2015, Vol. 114
the first drug with the introduction of the new drug
at a therapeutic dose (most appropriately used in
cases of acute psychosis in an inpatient setting), or
the original medication is slowly discontinued and
only when it is stopped will the next medication
be started (best used for those with a low risk of
relapse). With any switch of antipsychotic medication,
the individual is at heightened risk of a deterioration
and psychotic relapse or exacerbation, necessitating
a close monitoring of the individuals mental state
during this switching process.
Treatment-resistant schizophrenia
(TRS) and clozapine
Approximately 30% of patients with schizophrenia
will not respond to the use of FGAs or SGAs. The
failure to respond to two different antipsychotics, at
therapeutic doses and for a sufficient duration (gener-
ally taken to be 6-8 weeks of antipsychotic therapy)
means that a person meets the criteria for treatment
resistance. The only medication with proven effective-
ness in this subgroup of patients with TRS is clozapine.
In the UK, some 50–60% of patients will respond to
clozapine, with a 30% response rate achieved at 6
weeks of clozapine treatment and a higher response
rate achieved over longer treatment periods with up to
60–70% responding at 1 year.5 This prolonged period
of ongoing clinical response over the first year of treat-
ment is unique to clozapine among antipsychotic medi-
cations. It has been shown that clozapine does not
have superior efficacy in comparison with other anti-
psychotics in the treatment of first-episode psychosis,20
reinforcing the hypothesis that TRS constitutes a sub-
group schizophrenia patient population, with differ-
ences in pathological processes.
However, clozapine use varies widely depending
on geography, with the prevalence of clozapine use
being lower in most countries than the ∼30% of
patients who are likely to benefit from clozapine,
and substantial evidence exists that it is only used
after a delay of several years.21 This is partly due to
the nature and degree of side effects that it can cause,
including agranulocytosis, which affects some 0.8%
of patients prescribed clozapine and is associated
with a mortality of 1 in 10 000 of clozapine-treated
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173
patients in the UK. In the UK, clozapine is only pre-
scribed in conjunction with the weekly measurement
of the white cell count for the first 18 weeks of
treatment, followed by a fortnightly white cell count
measurement for the next 34 weeks and then fol-
lowed by monthly white cell counts for as long as the
patient is maintained on clozapine. It is likely that
the fear of adverse medication reactions (by clini-
cians and patients alike) and the inconvenience of
therapeutic monitoring of full blood counts (FBCs)
so early in the course of clozapine use are factors
contributing to this delay.
Clozapine is relatively free of EPSEs, though it
carries a heavy burden of other adverse reactions.
In addition to haematological adverse reactions, it
can also cause sedation, weight gain, constipation,
hypersalivation and rarely myocarditis and cardio-
myopathy. However, despite the high rate of adverse
effects associated with clozapine, there is evidence
that it is associated with reduced mortality compared
with other antipsychotics, with this reduction in
mortality not entirely explained by a reduction in
suicide risk.22
Medication non-adherence
Non-adherence to medication is more common in any
chronic illness, though rates of non-adherence are
higher in schizophrenia than other chronic illnesses.23
Non-adherence with antipsychotic treatment is high,
with up to 75% of patients at 2 years post hospital dis-
charge being non-adherent with antipsychotic medica-
tion.24 It can occur due to intolerable side effects, lack
of insight, the persistence of residual psychotic symp-
toms and poor therapeutic alliance. The discontinu-
ation of antipsychotics is associated with a worse
prognosis, with increased rates of relapse, rehospitali-
zation and suicide.25 Partial adherence with antipsy-
chotics is similarly associated with an increased risk of
relapse and rehospitalization, when compared with
complete medication adherence. Strategies to support
individual adherence with medication are important
to ensure that medication gaps are limited in order to
improve long-term prognosis. These interventions can
be particularly important in the early stages of the
illness, where medication partial or non-adherence
 174
can have devastating effects on the longer-term illness
course. Interventions include psychoeducation, motiv-
ational interviewing techniques, integration of the
importance of antipsychotic use into a relapse pre-
vention and recovery model, and a pharmacy-based
intervention consisting of easy-use packaging, refill
reminders and medication education.26
Long-acting injection (depot)
medications and combination/
high-dose therapy
The use of antipsychotic long-acting injections (LAIs)
(also known as depots) is recommended when a pat-
ient expresses a preference for this treatment or when
there is evidence of non-adherence with oral medica-
tions. The use of LAIs ensures that clinicians know
when a patient has taken medication or when they
stop it. It remains to be clearly established that LAIs
are more effective than oral antipsychotic medication,
though a recent meta-analysis indicated that LAIs had
reduced rates of relapse compared with oral antipsy-
chotics,8 with specific study designs tending to more
consistently support the effectiveness of LAIs. A
Finnish naturalistic study showed that the use of LAIs
led to a threefold reduction in the rates of rehospitali-
zation compared with the oral formulation of the
same antipsychotic.27 However, a recent large RCT
did not show superiority of risperidone LAI versus
oral medications.28
Pipotiazine palmitate (Piportil®) may be asso-
ciated with less-frequent EPSEs18 but is scheduled to
be withdrawn from the UK market and discontinued
in March 2015 (due to a global shortage of an active
ingredient of the compound).
There are four LAI formulations of SGAs, namely
risperidone, paliperidone, olanzapine embonate and ari-
piprazole; and four FGAs depot medications, namely
haloperidol decanoate, flupentixol decanoate, zuclo-
penthixol decanoate and fluphenazine decanoate.
Antipsychotic polypharmacy
Combination antipsychotic treatment (i.e. two or
more different antipsychotics), which is also known
as antipsychotic polypharmacy, is a frequently used
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practice. The reported prevalence of antipsychotic
polypharmacy ranges from 7 to 50%.29 There is often
a lack of clear pharmacological rationale for combin-
ing antipsychotics that provide the same putative anti-
psychotic dopamine D2 receptor blockade and little
information to know what the mechanism of action
of multiple antipsychotics in the brain is. Further,
combining antipsychotics can lead to high overall dose
and an increased burden of adverse effects, along with
an increased risk for drug–drug interactions, as well as
variability in serum levels and increased difficulty for
patients in remaining adherent to the treatment
regimen. There is no clear evidence to support combin-
ation antipsychotics,29 and it is best to reserve the use
of combination treatments for those who have a docu-
mented lack of response to antipsychotic monotherapy
and who may be intolerant of clozapine, thus restrict-
ing their access to this medication. If clinicians decide
to use combination antipsychotics, they should be
guided by the pharmacodynamic profiles of the com-
bined antipsychotics, with the aim of using antipsy-
chotics with differing receptor-binding profiles.
High-dose antipsychotic use
The majority of side effects associated with anti-
psychotic treatments are dose related, and the use of
high-dose antipsychotics [i.e. above British National
Formulary (BNF)-licensed maximum doses] is asso-
ciated with a higher rate of adverse effects (such as
sedation, constipation, postural hypotension, EPSEs,
QTc prolongation and sudden cardiac death). The
use of high-dose antipsychotic treatment should only
be used in exceptional circumstances, and care
should be taken if combination antipsychotics are
used, to ensure that the combined dose equivalence
is not >100% of the BNF-licenced maximum dose.
High-dose antipsychotic therapy is defined by the
Royal College of Psychiatrists (RCPsych) as a total
daily dose of a single antipsychotic that exceeds the
upper limit stated in the BNF, or a total daily dose of
two or more antipsychotics that exceeds the BNF
maximum as calculated by percentages using the
antipsychotic dose ready reckoner [example calcula-
tion: fluphenazine depot 100 mg monthly (50%)
and olanzapine 15 mg daily (75%) = 50% + 75% =
 Antipsychotic medication in schizophrenia, 2015, Vol. 114
125% (>100% therefore ‘high dose’)].30 For all
those treated with high-dose antipsychotics, it is
important to regularly monitor for metabolic abnor-
malities and for evidence of ECG changes, especially
QTc prolongation.
Clinical indications for antipsychotics
Antipsychotic medications are effective in a range of
disorders other than schizophrenia. In addition to
their antipsychotic effects, antipsychotics may also
have mood-stabilising, antimanic, antidepressant and
anxiolytic effects.
Bipolar affective disorder (BPAD)
Multiple international guidelines recommend the use
of antipsychotic medication in the treatment of all
stages of BPAD.18,31,32 For acute mania, antipsycho-
tics (particularly olanzapine, risperidone and quetia-
pine) along with mood stabilisers are consistently
identified as primary treatment options. A recent
meta-analysis identified that antipsychotics are more
effective than mood stabilisers in the treatment of
acute mania.33 Olanzapine and quetiapine are recom-
mended first-line treatments for bipolar depression.
Both quetiapine and olanzapine are associated with a
rapid onset of action in bipolar depression, with effi-
cacy demonstrated from the first week of treatment
onwards. In clinical practice, quetiapine is now con-
sidered more for its mood-stabilising properties than
for its antipsychotic effects. Similarly, the antipsycho-
tics that are indicated for acute mania are generally
recommended for maintenance therapy in BPAD.
Clozapine has evidence of effectiveness in refractory
mania and should be considered for this.
Unipolar depression
The use of antipsychotics as augmentation treatment
options in unipolar depression and anxiety disorders is
an off-label use, meaning that this use is not formally
licensed (but with a growing evidence base to indicate
the efficacy of certain antipsychotics). For treatment-
resistant unipolar depression (TRD), antipsychotics
are used as off-label augmentation strategies. There is
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175
evidence to support the use of quetiapine, aripiprazole,
olanzapine and risperidone as antidepressant augmen-
tation strategies in TRD, with the best evidence existing
for the use of quetiapine and aripiprazole.34 Quetia-
pine (150–300 mg daily) is licensed in the UK as an
antidepressant augmentation strategy.35 Antipsycho-
tics for augmentation in TRD are prescribed at lower
doses than what would be used in schizophrenia or
BPAD (e.g. olanzapine 5–12.5 mg/day, quetiapine
150–300 mg/day). In psychotic depression, the com-
bination of an antipsychotic and antidepressant is
more effective than the use of an antidepressant alone,
with olanzapine combined with fluoxetine probably
the best evidenced combination.36
Anxiety disorders
Antipsychotic medications have long been used as
augmentation strategies for anxiety disorders, with
the best evidence for their use as selective serotonin
reuptake inhibitor augmentation strategies in obses-
sive compulsive disorder (OCD) and for the use of
quetiapine in generalized anxiety disorder (GAD).37
Update on new antipsychotics
In the UK, several SGAs are now off patent, including
risperidone, olanzapine, amisulpride and quetiapine
(instant-release formulation). However, given the het-
erogeneous patient response to and tolerability of
antipsychotics, there remains a need to improve the
therapeutic efficacy of available agents and to aid
choice in improving treatment tolerability for patients.
The newer branded SGAs, asenapine and lurasidone,
have less impact on weight and metabolic parameters
than older agents such as olanzapine.
Paliperidone
Paliperidone is the active metabolite of risperidone
and is available in oral and LAI formulations, both
demonstrating efficacy and tolerability and a delay in
time to relapse in schizophrenia. It is not hepatically
metabolised, making it safe to use in hepatic impair-
ment and with limited risk of pharmacokinetic drug
interactions.18 Paliperidone is further licensed for the
 176
treatment of psychotic and manic symptoms of
schizoaffective disorder. Its adverse effect profile is
similar to that of the parent compound risperidone,
with increased weight gain, hyperprolactinaemia
and EPSEs at higher doses, along with case reports
of tardive dyskinesia.38 At doses of 9–12 mg of oral
paliperidone (equivalent to risperidone 4–6 mg
daily), the risk of EPSEs is increased. The therapeutic
dose range is 6–9 mg once daily (equivalent to risper-
idone 3–4 mg daily).18
Paliperidone palmitate is the LAI formulation,
which achieves active serum levels within days of ini-
tiation and allows deltoid, rather than gluteal muscle
administration.
Asenapine
Asenapine has demonstrated efficacy in the acute
and maintenance phases of schizophrenia treatment
and in the treatment of acute mania in BPAD, but it
is only currently licensed for the treatment of mania
in the UK.35 Asenapine has high affinity for multiple
serotonin receptors, with antagonism at 5-HT2A,
5-HT2C and 5-HT7 and 5-HT1A agonism, along
with potent D2 and D3 antagonism and some hista-
mine (H) 1 antagonism.18
Asenapine is subject to first-pass metabolism and
thus inactive if swallowed. It is, therefore, available
only as an orally disintegrating tablet, meaning that it
is absorbed via oral mucosa. This is in contrast to the
other antipsychotic orodispersible tablets of olanza-
pine, risperidone and aripiprazole, all of which must
be swallowed to be effective. This means that patients
must be informed that asenapine cannot be swallowed
and that food or drink must be avoided for at least 10
min after administration.
Asenapine does not require dose titration and can
be dosed at 5 mg bd for acute schizophrenia with doses
of up to 10 mg twice daily shown efficacy in preventing
relapses in schizophrenia. Asenapine has a half-life of
24 h and as such could theoretically be prescribed as a
once-daily medication, but the efficacy of a once-daily
prescription remains to be studied in trials. It appears
to be a metabolically neutral antipsychotic with low
propensity to cause weight gain (though some evidence
for a higher propensity for weight gain in acute mania
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exists) and has little effect on prolactin levels.39 It can
cause akathisia (increased occurrence at 10 mg twice-
daily dosing compared with 5 mg twice daily), sedation
and taste disturbance.40
Lurasidone
Lurasidone is licensed for the treatment of schizo-
phrenia35 and has shown efficacy as an adjunctive
treatment for bipolar depression, and it is a licensed
therapy for bipolar depression in the USA.
Lurasidone has full D2 antagonism and is an
antagonist at 5HT2A and 5HT7 receptors, with par-
tial agonism at 5-HT1A receptors, and with low af-
finity for 5HT2C, H1 and muscarinic receptors.40
Lurasidone is a once-daily prescription, simplifying its
administration. It is dosed in adults at 37 mg once
daily initially and increased if necessary to a maximum
of 148 mg once daily. For schizophrenia, a dose range
of 37–148 mg daily is recommended, with a lower dose
range of 18.5–120 mg daily, recommended for bipolar
depression (lurasidone at lower doses of 20–60 mg
daily has been shown to be as clinically efficacious in
bipolar depression, as at the higher dose range of 80–
100 mg/day). Lurasidone is metabolized by CYP3A4
enzymes, meaning that its dose should be reduced
when used with concomitant CYP3A4 inhibitors (e.g.
diltiazem, erythromycin).
Lurasidone is generally well tolerated, with low inci-
dences of weight gain and metabolic dysfunction. It is
associated with akathisia (increased incidence at doses
of 120 mg or greater), sedation and nausea, but simi-
larly to asenapine, despite been a full D2 antagonist, it
is not associated with higher incidences of EPSEs
(excluding akathisia) and hyperprolactinaemia.40
Conclusions
Maintaining the status Quo in antipsychotic
treatment
It remains the case that there has been no fundamen-
tal innovation in psychopharmacology for schizo-
phrenia since the discovery of clozapine in the late
1950s. This is further exacerbated by the recent
retreat of the pharmaceutical industry away from
 Antipsychotic medication in schizophrenia, 2015, Vol. 114
research and development in psychiatric disorders.
For all the benefits bought by antipsychotics and the
initially perceived advantages of SGAs, we are still
working with medications that are not fully effective
and often carry significant adverse effect burdens.
SGAs or FGAs?
Despite the lack of clear-cut differences in clinical
efficacy between SGAs and FGAs (with the exception
of clozapine), the introduction of the SGAs from
the early 1990s onwards represented meaningful
steps in attempting to improve pharmacotherapy for
patients with schizophrenia. While we are improving
our knowledge of what different treatments can and
cannot do,10 we still remain a long way from being
able to recommend with precision, specific treat-
ments for individual patients, in terms of the clinical
response and lack of adverse events. There is also no
longitudinal evidence to support attempts to identify
those patients who will and who will not require
long-term antipsychotic medication with FGAs or
SGAs.
Change in approach to medication
development
There is a growing consensus in academic psychiatry,
acknowledging that schizophrenia is not a single
disease entity and that the positive symptoms of psych-
osis (delusions, hallucinations) which antipsychotics
work best to treat, are only one aspect of the disorder’s
pathology. We need to focus future pharmaceutical
development on symptoms domains of schizophrenia,
with a particular need for treatments to target negative
symptoms and cognitive impairments in schizophrenia.
A more concentrated focus on the different symptom
domains may lead to endophenotypic markers being
identified for negative symptoms and cognitive deficits
(as well as for positive symptoms) that can promote
novel medication discovery. If medications are discov-
ered for separate symptom domains of schizophrenia,
then we could expect to be able to develop concurrent
medication strategies, with antipsychotics used in
combination with medications for negative symptoms
or along with those that have cognitive enhancing
effects.
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Novel therapeutic strategies
Our current level of knowledge regarding the patho-
genesis of schizophrenia continues to improve,
leading to the hope that in future novel therapeutics
that will rationally target cellular and molecular
targets, rather than just the D2 receptor, can be devel-
oped. All antipsychotic medications that have been
developed over the past six decades have been based
on the targeting of D2 receptors, and later the charac-
teristic 5-HT2A antagonism of SGAs. Future develop-
ments will target additional processes, including
glutamatergic, cholinergic and cannabinoid receptor
targets, and the emerging field of pharmacogenetics
will aim for treatments to be tailored to individual
patients in terms of efficacy and tolerability.
Conclusion
The heterogeneity in terms of individuals’ response
to antipsychotic treatment and the current inability
to predict response leads to a trial-and-error strategy
with treatment. It remains the case that we are no
closer to mirroring the effects of clozapine in TRS,
with its mechanism of action proving elusive to iden-
tify and replicate in other antipsychotic therapies
for schizophrenia.
Funding
Dr Lally and Dr MacCabe are both supported by
CRESTAR (CRESTAR project, http://www.crestar-
project.eu/) EU-FP7 grant number 279227; Dr
MacCabe is supported by STRATA (MRC grant no.
MR/L011794/) and by the National Institute for
Health Research (NIHR), Biomedical Research
Centre for Mental Health at the South London and
Maudsley NHS Foundation Trust and Institute of
Psychiatry, Psychology and Neuroscience, Kings
College London.
The views expressed are those of the authors and
not necessarily those of the NHS, the NIHR or the
Department of Health.
Conflict of Interest statement
None declared.
 178
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