Treatment of schizophrenia and related psychoses

These guidelines cover the management of schizophrenia. However, a diagnosis of schizophrenia is often made over a period of time so the 'Initial psychotic episode' guidance applies to pharmacologically treating brief psychotic episodes including drug-induced psychosis.

Psychological and psychosocial interventions should be offered to all people with schizophrenia, starting either during the acute phase (including in-patient settings) or later, but are beyond the scope of this guideline.

Guidance from an appropriate specialist mental health clinician should be sought in all instances of psychotic illness unless the practitioner is experienced at managing these conditions.

Initial psychotic episode

Offer oral antipsychotic medication. The choice of drug should be made jointly by the individual and healthcare professional, considering:

  • the likely effects of taking and not taking medication (including unpleasant subjective experiences)
  • long term treatment is required to prevent relapse
  • the views of the carer if the individual agrees
  • early treatment is associated with a better long term outcome
  • in the acute phase of illness, many antipsychotics have an immediate calming effect but there may be a delay by at least 2 weeks for the onset of antipsychotic action

There is no evidence of improved efficacy between first generation antipsychotic drugs and second-generation antipsychotics, with the exception of clozapine.

Use the most appropriate antipsychotic based on its side effect profile and licensed indications. Do not exceed BNF maximum doses. 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 BNF or SPC. Do not use loading doses of antipsychotic drugs. Carry out a trial of the medication at the optimum dosage for 4–6 weeks.

Risperidone is considered the treatment of choice if there is no preference between available antipsychotic treatments, based on clinical presentation and/ or individual preference.

  • 2mg in 1-2 divided doses on first day then 4mg in 1-2 divided doses on second day (slower titration may be required). Usual dose range 4mg - 6mg daily

See section 4.2 Drugs used in psychoses and related disorders

Acute management of psychotic illness

Acute psychosis is often accompanied by anxiety, and less often by behavioural disturbance. These symptoms are best dealt with by the concurrent prescription of a benzodiazepine e.g. diazepam 2-5mg up to three times daily. As the anxiety/behavioural disturbance settles the benzodiazepine should be reduced and discontinued.


Schizophrenia is associated with an increased incidence of diabetes and some second generation antipsychotics have been associated with increased rates of glucose intolerance and diabetes. It is advised that a specialist psychiatrist is consulted when treating people prescribed antipsychotics with newly emergent diabetes and commencing people on antipsychotics with existing diabetes.

Alternative antipsychotics

See section 4.2 Drugs used in psychoses and related disorders

See guidance below for alternative antipsychotics appropriate to be prescribed in certain circumstances or conditions. It is not a substitute for the BNF or SPC but can help guide the individual in their choice. (Adapted from Bazire; Psychotropic Drug Directory 2009)

  • Weight gain: Aripiprazole, Haloperidol, Risperidone
  • Cardiac Risk: Amisulpride, Quetiapine, Sulpiride
  • Old Age: Amisulpride, Aripiprazole, Risperidone, Sulpiride
  • Renal: All have moderate risk in renal impairment
    • Aripiprazole, Haloperidol
    • Recommend lower starting dose and titration rate: Olanzapine, Quetiapine
    • Up to 4mg daily: Risperidone
    • Once daily regimes: Sulpiride
  • Prolactin: Raised prolactin is associated with sexual dysfunction in men and amenorrhoea and lactation in women
    • Aripiprazole, Olanzapine, Quetiapine
  • Extrapyramidal Side-Effects:
    • Aripiprazole, Olanzapine, Quetiapine
    • Up to 6mg daily: Risperidone
  • Epilepsy: Amisulpride, Aripiprazole, Haloperidol, Risperidone, Sulpiride
  • Over- sedation:
    • Risperidone, quetiapine, sulpiride and haloperidol are associated with transient sedative properties
    • Amisulpride, Aripiprazole
  • Liver Impairment: Amisulpride, Aripiprazole, Haloperidol, Sulpiride

Subsequent episodes

Refer to the individual's history looking for previous evidence of successful pharmacological treatment. The same principles of individual-led choice apply in order to promote improved concordance with the prescribed regime. Take into account the clinical benefit and side effects experienced by the individual with any previous medication.

Prescribing antipsychotics for patients presenting with psychosis should be commenced after seeking specialist advice. However, you may wish to prescribe without seeking specialist advice if you feel confident in prescribing such medications in such circumstances, e.g. an existing patient suffering a recurrent acute episode previously managed on antipsychotic treatment.

Depot antipsychotics

When initiating depot/long-acting injectable antipsychotic medication:

  • take into account the individual's preferences and attitudes towards regular intramuscular injections and organisational procedures (for example, home visits and location of clinics)
  • take into account the same criteria recommended for the use of oral antipsychotic medication particularly in relation to the risks and benefits of the drug regimen e.g. explain risk of tardive dyskinesia
  • GP practices administering antipsychotic depot injections should have systems in place to identify and action missed doses

First generation depot antipsychotics (typical)

Flupentixol decanoate
Haloperidol decanoate
Pipotiazine palmitate
Zuclopenthixol decanoate

Consider offering depot antipsychotic medication to people with schizophrenia:

  • who would prefer such treatment after an acute episode OR
  • non-adherence to antipsychotic medication

Initially use a small test dose as set out in the BNF or SPC.

Pipotiazine depot injection will be discontinued from the end of March 2015. No new patients will receive pipotiazine. Patients currently receiving pipotiazine will be switched to an alternative treatment.

See section 4.2 Drugs used in psychoses and related disorders

Atypical depot antipsychotic

Olanzapine pamoate
Paliperidone palmitate

Long-acting aripiprazole, olanzapine and paliperidone injections are currently approved as hospital only drugs until other service arrangements are in place.

Specific indications for these medications in people with schizophrenia are:

  • Non-adherence to antipsychotic medication OR
  • First generation ('typical') depot injections are not clinically appropriate
Treatment initiation should be in accordance with the SPC:
  • Aripiprazole long-acting injection: trial of oral aripiprazole before initiating treatment with the injection. Continue treatment with oral aripiprazole for the first 2 weeks of treatment with injection.
  • Olanzapine long-acting injection: trial of oral olanzapine before initiating treatment with the injection. Olanzapine long-acting injection is associated with post-injection syndrome:
    • Olanzapine should only be given in health-care facilities where administration of the injection and observation of patients post-injection can be undertaken safely and for at least three hours. The three hour observation period should be extended as clinically appropriate for patients who exhibit any signs or symptoms consistent with olanzapine overdose.
    • Olanzapine should only be administered by healthcare professionals trained in the appropriate injection technique. Training materials are available at:
  • Paliperidone long-acting injection: trial of oral risperidone or oral paliperidone before initiating treatment with the injection. Note that oral paliperidone is not listed as a formulary option.
  • No new patients will receive risperidone long-acting injection. There is an existing cohort of patients who will continue to receive risperidone.
  • Staff administering the injection should receive appropriate training from someone familiar with its correct preparation and the injection should be stored in a fridge. Once it is exposed to temperatures above 8°C then the shelf-life is reduced to 7 days (at room temperature or in fridge)

See section 4.2 Drugs used in psychoses and related disorders

Combinations of antipsychotics

Do not use combinations of two or more antipsychotics except where:

  • Cross-tapering between two different antipsychotics and only then for a short time.
  • Augmenting clozapine with an evidence-based antipsychotic agent which does not compound the side effects of the clozapine; e.g. risperidone, sulpiride or aripiprazole

Patients unresponsive to treatment

For people with schizophrenia whose illness has not responded adequately to pharmacological or psychological treatment:

  • review the diagnosis
  • establish that there has been adherence to antipsychotic medication, prescribed at an adequate dose and for the correct duration
  • review engagement with and use of psychological treatments
  • consider other causes of non-response, such as comorbid substance misuse (including alcohol), the concurrent use of other prescribed medication or physical illness


Clozapine (See section 4.2 Drugs used in psychoses and related disorders) may be offered 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 atypical antipsychotic.

For people with schizophrenia whose illness has not responded adequately to clozapine at an optimised dose, healthcare professionals should consider the points above (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.

Monitoring and stopping treatment

Patients with schizophrenia should have physical health monitoring at least once a year.

Focus on cardiovascular disease risk assessment but bear in mind that people with schizophrenia are at a higher risk of CVD than the general population.

  • Monitor increased risk of cardiovascular disease, assess
    • Smoking Status
    • Alcohol consumption
    • Blood Pressure
    • BMI or other measure of obesity
    • Fasting total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides
    • Fasting blood glucose
    • Renal Function
    • Liver Function (transaminases)
    • Thyroid Stimulating Hormone if dyslipidaemia present
  • Promote healthy lifestyle, for example good diet, exercise and smoking cessation
  • Monitor side effects
    • Extrapyramidal side effects/Tardive Dyskinesia
    • Other endocrine disorders e.g. high prolactin
    • Sexual dysfunction


Inform the individual that there is a high risk of relapse if they stop medication in the next 1–2 years. If antipsychotic medication has to be withdrawn, reduce the dose gradually and monitor regularly for signs and symptoms of relapse. After withdrawal from antipsychotic medication, continue monitoring for signs and symptoms of relapse for at least 2 years.

In cases of acute and severe adverse effects (i.e. blood dyscrasia with clozapine) where abrupt discontinuation of medication is required, specialist advice should be sought to ensure adequate support is available and to ensure an urgent review of treatment is completed.

Elderly patients

Prescribing for elderly patients – start low and go slow. The lowest effective dosage of medications should be used, monitor frequently

Patients aged over 65 years of age have an increased sensitivity to medications as a result of age–related alterations in pharmacodynamics (changes in neuronal cell numbers, receptors and receptor binding) and pharmacokinetics (changes in absorption, distribution, metabolism, excretion and protein binding). Especially significant is the reduced liver metabolism and declining renal clearance, associated with increasing age.

Avoid polypharmacy; the elderly are at increased risk of adverse neuropsychiatric complications from drug interactions. Consider the possibility of concomitant use of over the counter (OTC) medications. Always consider drug toxicity when the patient exhibits alterations in attention or cognitive or any behavioural change.

Avoid the use of drugs which put the elderly at risk of falls, especially sedative hypnotics, benzodiazepines, phenobarbital, phenytoin.

Choice of psychotropics in the elderly

The elderly are much more sensitive to orthostatic hypotension and anticholinergic effects. Drugs with a high degree of anticholinergic activity should be avoided. Tricyclics should be used with caution, especially those with a higher degree of anticholinergic activity, for example, amitriptyline. Selective serotonin re-uptake inhibitors are better tolerated.

Electroconvulsive therapy (ECT) is a safe and effective treatment option in this population for severe depression and mania.

Lithium clearance is reduced in the elderly and lithium toxicity may occur at levels that would be considered “therapeutic" in younger patients. Required doses may be up to 50% lower compared with younger patients.

Choice of antipsychotics in the elderly

The elderly are more susceptible to the extrapyramidal symptoms of antipsychotics as well as to the orthostatic hypotension and cholinergic effects of these agents. When indicated, they should be used in much lower doses (generally one half to one third of doses in younger adults) and titrated more slowly with frequent monitoring. Overall atypical antipsychotics have a more favourable side effect profile compared to traditional antipsychotics.

There is a 3-fold increased risk of cerebrovascular adverse events in people with dementia treated with the atypical antipsychotics, risperidone and olanzapine. The CSM advises 'potentially similar risk' of increase in cerebrovascular adverse events with quetiapine but there are no studies confirming this.

Pregnancy and breastfeeding

Seek expert advice, the National Teratology Information Service offers up-to-date information on all medicines in pregnancy. Tel: 0844 892 0909 (8.30 – 17.00 Monday to Friday)

Risks to consider

  • Raised prolactin levels with some antipsychotics (amisulpride, risperidone, sulpiride)
  • Gestational diabetes and weight gain with olanzapine
  • Agranulocytosis in the foetus (theoretical) and breastfed infant with clozapine
  • Extrapyramidal symptoms in the neonate especially with depot medication (these are usually self-limiting)

Actions to take

  • Advise women taking antipsychotics who are planning a pregnancy that raised prolactin levels reduce the chances of conception. If levels are raised, consider an alternative drug
  • If prescribing olanzapine to a pregnant woman, consider risk factors for gestational diabetes and weight gain, including family history, existing weight and ethnicity

Do not routinely prescribe:

  • Clozapine to women who are pregnant or breastfeeding; for those taking it, consider switching to another drug and monitor carefully
  • Depot antipsychotics to pregnant women
  • Anticholinergic drugs for extrapyramidal side effects of antipsychotics, except for short-term use; instead, adjust dose and timing of the antipsychotic or switch to another drug to avoid side effects

Patient focussed resources

A patient decision aid(which includes information on relative side effects but also some non-formulary treatments) is available from Choice and Medication.

Royal College of Psychiatrists Schizophrenia leaflet (available in several languages).


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