Antipsychotic drugs (also known as ‘neuroleptics’) have a wide variety of uses in psychiatric practice. The main uses of antipsychotic drugs include the treatment of:

There are also several non-psychotic uses for antipsychotic drugs, which should be borne in mind when seeing patients. For example, in dermatological practice, ‘off-label’ prescribing of antipsychotic drugs sometimes occurs for conditions such as pruritus, neurotic excoriations and pathological skin picking, trichotillomania, and cutaneous pain syndromes (including postherpetic neuralgia) (Koo & Ng, 2002).

In general, the older, first-generation, or typical, antipsychotic drugs exhibit antagonistic activity at brain dopaminergic D2 receptors. The main groups are as follows.

In general, the newer, second-generation, or atypical, antipsychotic drugs are associated with less frequent extrapyramidal side-effects than the firstgeneration antipsychotics. The second-generation antipsychotic drugs currently in routine use in the UK are:

Clozapine is a dibenzodiazepine and is the archetypal atypical antipsychotic; olanzapine and quetiapine have similar molecular structures. Aripiprazole is a quinolinone derivative while risperidone is a benzisoxazole and paliperidone is an active metabolite of risperidone (paliperidone is 9-hydroxyrisperidone).

In 2009, the National Institute for Health and Clinical Excellence, known as NICE, which is an independent UK organization responsible for providing national guidance on the promotion of good health and the prevention and treatment of ill health, issued the following guidance on pharmacological interventions for patients suffering from schizophrenia.

‘For people with newly diagnosed schizophrenia, offer oral antipsychotic medication. Provide information and discuss the benefits and side-effect profile of each drug with the service user. The choice of drug should be made by the service user and healthcare professional together, considering:

Before starting antipsychotic medication, NICE recommend that an electrocardiogram should be carried out if any of the following criteria is met:

CATIE and CUtLASS refer to two large studies comparing first-generation antipsychotics with second-generation antipsychotics; both studies were funded independently of pharmaceutical companies. CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) was funded by the National Institute of Mental Health (NIMH) and compared the second-generation antipsychotics olanzapine, quetiapine, risperidone and ziprasidone (included in the study after its approval by the US Food and Drug Administration) and the first-generation antipsychotic perphenazine. Almost 1500 patients with chronic schizophrenia were randomly assigned to treatment with one of these antipsychotic drugs in a double-blind design, with the primary outcome measure being discontinuation of treatment for any cause (Lieberman et al., 2005). The surprising conclusions of this study were as follows: ‘The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism.’

CUtLASS (Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Study) was funded by the Health Technology Assessment Programme and compared first-generation antipsychotics and second-generation antipsychotics (apart from clozapine). 227 patients with schizophrenia and related disorders were assessed for medication review because of inadequate response or adverse effects; the patients were randomly prescribed either first-generation antipsychotics or second-generation antipsychotics (other than clozapine), with the individual medication choice in each arm being made by the patients’ psychiatrists (Jones et al., 2006). The study found that patients in the first-generation antipsychotic arm showed a trend toward greater improvement in Quality of Life Scale and symptom scores, and overall patients reported no clear preference for either group of antipsychotics. The authors concluded that: ‘In people with schizophrenia whose medication is changed for clinical reasons, there is no disadvantage across 1 year in terms of quality of life, symptoms, or associated costs of care in using [first-generation antipsychotics] rather than nonclozapine [second-generation antipsychotics]. Neither inadequate power nor patterns of drug discontinuation accounted for the result.’

Owens (2011) has recently commented as follows on the implications of these two major studies: ‘Antipsychotic choices should be based on an ‘individual risk:benefit appraisal’, where the particular illness, then the individual patient and finally individual drug variables are considered in turn for treatment that is truly ‘tailored’. Now, the entire repertoire of antipsychotics can be opened up to equal consideration.

Alas, a whole generation has matured through the specialist ranks with little or no exposure to older antipsychotics. For them, Stelazine [trifluoperazine] might as well be a fizzy drink! A major educational undertaking is necessary.’

Equivalent doses for a selection of orally administered antipsychotic drugs are given in the British National Formulary, 62nd edition, and reproduced in Table 3.2. They are intended only as an approximate guide. Note that these equivalent doses should not be extrapolated beyond the maximum dose for each antipsychotic drug.

In the UK, antipsychotic doses which exceed those given in the latest British National Formulary are unlicensed. The Royal College of Psychiatrists have issued the following advice on doses exceeding the British National Formulary upper limits.

In addition, the British National Formulary offers the following advice:

‘Important: When prescribing an antipsychotic for administration on an emergency basis, the intramuscular dose should be lower than the corresponding oral dose (owing to absence of first-pass effect), particularly if the patient is very active (increased blood flow to muscle considerably increases the rate of absorption). The prescription should specify the dose for each route and should not imply that the same dose can be given by mouth or by intramuscular injection. The dose of antipsychotic for emergency use should be reviewed at least daily.’

Following long-term antipsychotic drug pharmacotherapy, withdrawal of the drug should take place gradually and under close medical supervision. It is particularly important to look out for evidence of withdrawal syndromes or relapse of the psychiatric illness (for up to 2 years following antipsychotic withdrawal).

This is a medical emergency that is life-threatening and requires immediate treatment.

David Lewis’ group have found that chronic exposure (over 17-27 months) of macaque monkeys to the orally administered antipsychotic drugs haloperidol or olanzapine, with plasma antipsychotic levels comparable to those achieved in human patients treated with these drugs for schizophrenia, is associated with reduced brain volume (Dorph-Petersen et al., 2005), compared with a third group which received sham treatment. This group also reported a statistically significant 21% lower astrocyte number and a non-significant 13% lower oligodendrocyte number in the grey matter in the antipsychotic-exposed monkeys (the haloperidol and olanzapine groups were similar) (Konopaske et al., 2008). It is noteworthy that these findings are consistent with reports from some post-mortem studies in schizophrenia (Puri, 2011).

From the large cohort of schizophrenia patients who have undergone longitudinal MRI examinations in the Iowa Longitudinal Study, significant progressive brain changes, associated with antipsychotic use, were found in most brain regions (Ho et al., 2011). These have been summarized by Puri (2011):

‘[These changes included] reductions in volume in: total cerebral tissue; total cerebral grey matter; frontal grey matter; temporal grey matter; parietal grey matter; caudate; putamen; and thalamus. Significant increases in volume were found in: parietal white matter; lateral ventricles; and sulcal cerebrospinal fluid (CSF). After adjusting for the potential confounding effects of the other three predictor variables [follow-up duration, illness severity and alcohol or illicit drug misuse], antipsychotic treatment was found to have significant main effects on total cerebral and lobar grey matter and putamen volumes; higher antipsychotic medication dose was associated with smaller total cerebral, frontal, temporal, and parietal grey matter volumes (all independent of follow-up duration), and with a larger putamen volume. Significant treatment × time interaction effects were found for total cerebral tissue volumes, total cerebral and lobar white matter, lateral ventricular, sulcal CSF, caudate, putamen, and cerebellar volumes. Greater antipsychotic dose was associated with greater reduction in white matter, caudate, and cerebellar volumes over time, and with greater CSF volume and putamen enlargement. There were no significant main effects of the severity of alcohol or illicit substance misuse on brain volume changes apart from the lateral ventricles (increased in size) and the cerebellar volumes (decreased).’

The group also examined the issue of whether any particular type of antipsychotic drug was particularly associated with changes in brain structure (or, indeed, a lack of such an association). They split the antipsychotic drugs into the following three groups: first-generation antipsychotics, clozapine, and non-clozapine second-generation antipsychotics (Ho et al. 2011). These results have been summarized by Puri (2011):

‘All three classes of drug were found to be associated with significant changes in brain volumes. Higher typical antipsychotic doses were
associated with smaller total cerebral grey matter and frontal grey matter volumes and with higher putamen volumes; higher doses of non-clozapine atypical antipsychotics were associated with lower frontal and parietal grey matter volumes and with higher parietal white matter, caudate, and putamen volumes; higher clozapine doses were associated with smaller total cerebral and lobar grey matter volumes and with larger sulcal CSF volumes and smaller caudate, putamen, and thalamic volumes.’

The British National Formulary points out that antipsychotics are associated, in elderly patients with dementia, with ‘a small increased risk of mortality and an increased risk of stroke or transient ischaemic attack.’ It also points out that elderly patients have a particular susceptibility to:

The British National Formulary recommends the following in respect of antipsychotic medication in elderly patients.