Drug reference
Control of deviant antisocial sexual behaviour ▶BY MOUTH ▶Adult: 0.25–1.5 mg daily in divided doses, adjusted according to response, for debilitated patients, use elderly dose ▶Elderly: Initially 0.125–0.75 mg daily in divided doses, adjusted according to response
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CNS depression. comatose states. phaeochromocytoma
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Risk factors for stroke Blood dyscrasias. cardiovascular disease. conditions predisposing to seizures. depression. diabetes (may raise blood glucose). epilepsy. history of jaundice. myasthenia gravis. Parkinson’s disease (may be exacerbated)(in adults). photosensitisation (may occur with higher dosages). prostatic hypertrophy (in adults). severe respiratory disease. susceptibility to angle-closure glaucoma CAUTIONS, FURTHER INFORMATION ▶Cardiovascular disease An ECG may be required, particularly if physical examination identifies cardiovascular risk factors, personal history of cardiovascular disease, or if the patient is being admitted as an inpatient. ▶Elderly Prescription potentially inappropriate (STOPP criteria): . for all antipsychotics (other than quetiapine and clozapine) in patients with parkinsonism or Lewy Body Disease (risk of severe extrapyramidal symptoms) . in behavioural and psychological symptoms of dementia (BPSD), unless symptoms are severe and other non- pharmacological treatments have failed (increased risk of stroke) . for use as a hypnotic, unless sleep disorder is due to psychosis or dementia (risk of confusion, hypotension, extrapyramidal side-effects and falls) . in patients prone to falls (may cause gait dyspraxia, parkinsonism) . if prescribed a phenothiazine (other than prochlorperazine for nausea, vomiting or vertigo; chlorpromazine for relief of persistent hiccups; levomepromazine as an antiemetic in palliative care) as first-line treatment (sedative, significant antimuscarinic (anticholinergic) toxicity in older people, and safer and more efficacious alternatives exist)— . if prescribed an antipsychotic drug with moderate or marked antimuscarinic effects (e.g. chlorpromazine, clozapine, flupenthixol, fluphenazine, pipothiazine, promazine and zuclopenthixol) in patients with a history of prostatism or urinary retention (high risk of urinary retention). See also Prescribing in the elderly p. 33.
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The proprietary name Benquil ® has been used for benperidol tablets. Patient decision aid ▶In adults Antipsychotic medicines for treating agitation, aggression and distress in people living with dementia. National Institute for Health and Care Excellence. June 2018. www.nice.org.uk/about/what-we-do/our-programmes/ nice-guidance/nice-guidelines/shared-decision-making
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→Appendix 1: benperidol
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Appetite decreased. blood disorder. cardiac arrest. confusion. depression. dyspepsia. headache. hepatic disorders. hyperhidrosis. hypersalivation. hypertension. muscle rigidity. nausea. oculogyric crisis. oedema. oligomenorrhoea. paradoxical drug reaction. pruritus. psychiatric disorder. temperature regulation disorders. weight change ▶Common or very common Agitation. amenorrhoea. arrhythmias. constipation. dizziness. drowsiness. dry mouth. erectile dysfunction. galactorrhoea. gynaecomastia. hyperprolactinaemia. hypotension (dose- related). insomnia. leucopenia. movement disorders. neutropenia. parkinsonism. QT interval prolongation. Nervous system rash. seizure. tremor. urinary retention. vomiting. weight increased ▶Uncommon Agranulocytosis. embolism and thrombosis. neuroleptic malignant syndrome (discontinue—potentially fatal) ▶Rare or very rare Sudden death. withdrawal syndrome neonatal SIDE-EFFECTS, FURTHER INFORMATION For depot antipsychotics—side-effects may persist until the drug has been cleared from its depot site. Overdose Phenothiazines cause less depression of consciousness and respiration than other sedatives. Hypotension, hypothermia, sinus tachycardia, and arrhythmias may complicate poisoning. For details on the management of poisoning see Antipsychotics under Emergency treatment of poisoning p. 1430.
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Extrapyramidal effects and withdrawal syndrome have been reported occasionally in the neonate when antipsychotic drugs are taken during the third trimester of pregnancy. Following maternal use of antipsychotic drugs in the third trimester, neonates should be monitored for symptoms including agitation, hypertonia, hypotonia, tremor, drowsiness, feeding problems, and respiratory distress. Extrapyramidal effects and withdrawal syndrome have been reported occasionally in the neonate when antipsychotic drugs are taken during the third trimester of pregnancy. Following maternal use of antipsychotic drugs in the third trimester, neonates should be monitored for symptoms including agitation, hypertonia, hypotonia, tremor, drowsiness, feeding problems, and respiratory distress.
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There is limited information available on the short- and long-term effects of antipsychotic drugs on the breast-fed infant. Animal studies indicate possible adverse effects of antipsychotic medicines on the developing nervous system. Chronic treatment with antipsychotic drugs whilst breast-feeding should be avoided unless absolutely necessary. There is limited information available on the short- and long-term effects of antipsychotic drugs on the breast-fed infant. Animal studies indicate possible adverse effects of antipsychotic medicines on the developing nervous system. Chronic treatment with antipsychotic drugs whilst breast-feeding should be avoided unless absolutely necessary. Phenothiazine derivatives are sometimes used in breast-feeding women for short-term treatment of nausea and vomiting.
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Manufacturer advises caution.
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Dose adjustments Start with small doses in severe renal impairment because of increased cerebral sensitivity.
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Manufacturer advises regular blood counts and liver function tests during long- term treatment. ▶It is advisable to monitor prolactin concentration at the start of therapy, at 6 months, and then yearly. Patients taking antipsychotic drugs not normally associated with symptomatic hyperprolactinaemia should be considered for prolactin monitoring if they show symptoms of hyperprolactinaemia (such as breast enlargement and galactorrhoea). ▶Patients with schizophrenia should have physical health monitoring (including cardiovascular disease risk assessment) at least once per year. ▶In children Regular clinical monitoring of endocrine function should be considered when children are taking an antipsychotic drug known to increase prolactin levels; this includes measuring weight and height, assessing sexual maturation, and monitoring menstrual function.
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There can be variation in the licensing of different medicines containing the same drug. Forms available from special-order manufacturers include: oral suspension Tablet CAUTIONARY AND ADVISORY LABELS 2 ▶Anquil (Kyowa Kirin Ltd) Benperidol 250 microgram Anquil 250microgram tablets | 112 tablet P £117.31 DT = £117.31 3.6 Psychoses and schizophrenia Psychoses and related disorders Advice of Royal College of Psychiatrists on doses of antipsychotic drugs above BNF upper limit Unless otherwise stated, doses in the BNF are licensed doses—any higher dose is therefore unlicensed . Consider alternative approaches including adjuvant therapy and newer or second-generation antipsychotic drugs such as clozapine. . Bear in mind risk factors, including obesity; particular caution is indicated in older patients, especially those over 70. . Consider potential for drug interactions—see interactions: Appendix 1 (antipsychotics). . Carry out ECG to exclude untoward abnormalities such as prolonged QT interval; repeat ECG periodically and reduce dose if prolonged QT interval or other adverse cardiac abnormality develops. . Increase dose slowly and not more often than once weekly. . Carry out regular pulse, blood pressure, and temperature checks; ensure that patient maintains adequate fluid intake. . Consider high-dose therapy to be for limited period and review regularly; abandon if no improvement after 3 months (return to standard dosage). 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. Antipsychotic drugs Antipsychotic drugs are also known as ‘neuroleptics’ and (misleadingly) as ‘major tranquillisers’. In the short term they are used to calm disturbed patients whatever the underlying psychopathology, which may be schizophrenia, brain damage, mania, toxic delirium, or agitated depression. Antipsychotic drugs are used to alleviate severe anxiety but this too should be a short-term measure. Schizophrenia The aim of treatment is to alleviate the suffering of the patient (and carer) and to improve social and cognitive functioning. Many patients require life-long treatment with antipsychotic medication. Antipsychotic drugs relieve positive psychotic symptoms such as thought disorder, hallucinations, and delusions, and prevent relapse; they are usually less effective on negative symptoms such as apathy and social withdrawal. In many patients, negative symptoms persist between episodes of treated positive symptoms, but earlier treatment of psychotic illness may protect against the development of negative symptoms over time. Patients with acute schizophrenia generally respond better than those with chronic symptoms. Long-term treatment of a patient with a definitive diagnosis of schizophrenia is usually required after the first episode of illness in order to prevent relapses. Doses that are effective in acute episodes should generally be continued as prophylaxis. First-generation antipsychotic drugs The first-generation antipsychotic drugs act predominantly by blocking dopamine D2 receptors in the brain. First- generation antipsychotic drugs are not selective for any of the four dopamine pathways in the brain and so can cause a range of side-effects, particularly extrapyramidal symptoms and elevated prolactin. The phenothiazine derivatives can Nervous system be divided into 3 main groups: . Group 1: chlorpromazine hydrochloride p. 402, levomepromazine p. 460, and promazine hydrochloride p. 424, generally characterised by pronounced sedative effects and moderate antimuscarinic and extrapyramidal side-effects. . Group 2: pericyazine p. 406, generally characterised by moderate sedative effects, but fewer extrapyramidal side- effects than groups 1 or 3. . Group 3: fluphenazine decanoate p. 410, perphenazine, prochlorperazine p. 407, and trifluoperazine p. 408, generally characterised by fewer sedative and antimuscarinic effects, but more pronounced extrapyramidal side-effects than groups 1 and 2. Butyrophenones (benperidol p. 398 and haloperidol p. 404) resemble the group 3 phenothiazines in their clinical properties. Thioxanthenes (flupentixol p. 403 and zuclopenthixol p. 409) have moderate sedative, antimuscarinic effects, and extrapyramidal effects. Diphenylbutylpiperidines (pimozide p. 406) and the substituted benzamides (sulpiride p. 408) have reduced sedative, antimuscarinic, and extrapyramidal effects. Second-generation antipsychotic drugs The second-generation antipsychotic drugs (sometimes referred to as atypical antipsychotic drugs) act on a range of receptors in comparison to first-generation antipsychotic drugs and have more distinct clinical profiles, particularly with regard to side-effects. Prescribing for the elderly The balance of risks and benefit should be considered before prescribing antipsychotic drugs for elderly patients. In elderly patients with dementia, antipsychotic drugs are associated with a small increased risk of mortality and an increased risk of stroke or transient ischaemic attack (see Dementia p. 315). Furthermore, elderly patients are particularly susceptible to postural hypotension and to hyper- and hypothermia in hot or cold weather. It is recommended that: . Antipsychotic drugs should not be used in elderly patients to treat mild to moderate psychotic symptoms. . Initial doses of antipsychotic drugs in elderly patients should be reduced (to half the adult dose or less), taking into account factors such as the patient’s weight, co- morbidity, and concomitant medication. . Treatment should be reviewed regularly. Prescribing of antipsychotic drugs in patients with learning disabilities g When prescribing for patients with learning disabilities who are prescribed antipsychotic drugs and who are not experiencing psychotic symptoms, the following considerations should be taken into account: . a reduction in dose or the discontinuation of long-term antipsychotic treatment; . review of the patient’s condition after dose reduction or discontinuation of an antipsychotic drug; . referral to a psychiatrist experienced in working with patients who have learning disabilities and mental health problems; . annual documentation of the reasons for continuing a prescription if the antipsychotic is not reduced in dose or discontinued h. Side effects of antipsychotic drugs Side-effects caused by antipsychotic drugs are common and contribute significantly to non-adherence to therapy. Extrapyramidal symptoms Extrapyramidal symptoms occur most frequently with the piperazine phenothiazines (fluphenazine, perphenazine, prochlorperazine, and trifluoperazine), the butyrophenones Nervous system (benperidol and haloperidol), and the first-generation depot preparations. They are easy to recognise but cannot be predicted accurately because they depend on the dose, the type of drug, and on individual susceptibility. Extrapyramidal symptoms consist of: . parkinsonian symptoms (including tremor), which may occur more commonly in adults or the elderly and may appear gradually; . dystonia (abnormal face and body movements) and dyskinesia, which occur more commonly in children or young adults and appear after only a few doses; . akathisia (restlessness), which characteristically occurs after large initial doses and may resemble an exacerbation of the condition being treated; . tardive dyskinesia (rhythmic, involuntary movements of tongue, face, and jaw), which usually develops on long- term therapy or with high dosage, but it may develop on short-term treatment with low doses—short-lived tardive dyskinesia may occur after withdrawal of the drug. Parkinsonian symptoms remit if the drug is withdrawn and may be suppressed by the administration of antimuscarinic drugs. However, routine administration of such drugs is not justified because not all patients are affected and they may unmask or worsen tardive dyskinesia. Tardive dyskinesia is the most serious manifestation of extrapyramidal symptoms; it is of particular concern because it may be irreversible on withdrawing therapy and treatment is usually ineffective. In children, tardive dyskinesia is more likely to occur when the antipsychotic drug is withdrawn. However, some manufacturers suggest that drug withdrawal at the earliest signs of tardive dyskinesia (fine vermicular movements of the tongue) may halt its full development. Tardive dyskinesia occurs fairly frequently, especially in the elderly, and treatment must be carefully and regularly reviewed. Hyperprolactinaemia Most antipsychotic drugs, both first- and second-generation, increase prolactin concentration to some extent because dopamine inhibits prolactin release. Aripiprazole reduces prolactin because it is a dopamine-receptor partial agonist. Risperidone, amisulpride, and first-generation antipsychotic drugs are most likely to cause symptomatic hyperprolactinaemia. The clinical symptoms of hyperprolactinaemia include sexual dysfunction, reduced bone mineral density, menstrual disturbances, breast enlargement, and galactorrhoea. Sexual dysfunction Sexual dysfunction is one of the main causes of non- adherence to antipsychotic medication; physical illness, psychiatric illness, and substance misuse are contributing factors. Antipsychotic-induced sexual dysfunction is caused by more than one mechanism. Reduced dopamine transmission and hyperprolactinaemia decrease libido; antimuscarinic effects can cause disorders of arousal; and alpha1-adrenoceptor antagonists are associated with erection and ejaculation problems in men. Risperidone and haloperidol commonly cause sexual dysfunction. If sexual dysfunction is thought to be antipsychotic-induced, dose reduction or switching medication should be considered. Cardiovascular side-effects Antipsychotic drugs have been associated with cardiovascular side-effects such as tachycardia, arrhythmias, and hypotension. QT-interval prolongation is a particular concern with pimozide and haloperidol. There is also a higher probability of QT-interval prolongation in patients using any intravenous antipsychotic drug, or any antipsychotic drug or combination of antipsychotic drugs with doses exceeding the recommended maximum. Cases of sudden death have occurred. Hyperglycaemia and weight gain Hyperglycaemia, and sometimes diabetes, can occur with antipsychotic drugs, particularly clozapine, olanzapine, quetiapine, and risperidone. All antipsychotic drugs may cause weight gain, but the risk and extent varies. Clozapine and olanzapine commonly cause weight gain. Hypotension and interference with temperature regulation Hypotension and interference with temperature regulation are dose-related side-effects that are liable to cause dangerous falls and hypothermia or hyperthermia in the elderly. Clozapine, chlorpromazine, lurasidone, and quetiapine can cause postural hypotension (especially during initial dose titration) which may be associated with syncope or reflex tachycardia in some patients. Neuroleptic malignant syndrome Neuroleptic malignant syndrome (hyperthermia, fluctuating level of consciousness, muscle rigidity, and autonomic dysfunction with pallor, tachycardia, labile blood pressure, sweating, and urinary incontinence) is a rare but potentially fatal side-effect of all antipsychotic drugs. Discontinuation of the antipsychotic drug is essential because there is no proven effective treatment, but bromocriptine and dantrolene have been used. The syndrome, which usually lasts for 5–7 days after drug discontinuation, may be unduly prolonged if depot preparations have been used. Blood dyscrasias Perform blood counts if unexplained infection or fever develops. Choice There is little meaningful difference in efficacy between each of the antipsychotic drugs (other than clozapine p. 414), and response and tolerability to each antipsychotic drug varies. There is no first-line antipsychotic drug which is suitable for all patients. Choice of antipsychotic medication is influenced by the patient’s medication history, the degree of sedation required (although tolerance to this usually develops), and consideration of individual patient factors such as risk of extrapyramidal side-effects, weight gain, impaired glucose tolerance, QT-interval prolongation, or the presence of negative symptoms. Negative symptoms Second generation antipsychotic drugs may be better at treating the negative symptoms of schizophrenia. Extrapyramidal side-effects Second-generation antipsychotic drugs should be prescribed if extrapyramidal side-effects are a particular concern. Of these, aripiprazole p. 413, clozapine, olanzapine p. 416, and quetiapine p. 419 are least likely to cause extrapyramidal side-effects. Although amisulpride p. 412 is a dopamine- receptor antagonist, extrapyramidal side-effects are less common than with the first-generation antipsychotic drugs because amisulpride selectively blocks mesolimbic dopamine receptors, and extrapyramidal symptoms are caused by blockade of the striatal dopamine pathway. QT interval Aripiprazole has negligible effect on the QT interval. Other antipsychotic drugs with a reduced tendency to prolong QT interval include amisulpride, clozapine, flupentixol p. 403, fluphenazine decanoate p. 410, olanzapine, perphenazine, prochlorperazine p. 407, risperidone p. 421, and sulpiride p. 408. Diabetes Schizophrenia is associated with insulin resistance and diabetes; the risk of diabetes is increased in patients with schizophrenia who take antipsychotic drugs. First- generation antipsychotic drugs are less likely to cause diabetes than second-generation antipsychotic drugs, and of the first-generation antipsychotic drugs, fluphenazine decanoate and haloperidol p. 404 are lowest risk. Amisulpride and aripiprazole have the lowest risk of diabetes of the second-generation antipsychotic drugs. Amisulpride, aripiprazole, haloperidol, sulpiride, and trifluoperazine p. 408 are least likely to cause weight gain. Sexual dysfunction and prolactin The antipsychotic drugs with the lowest risk of sexual dysfunction are aripiprazole and quetiapine. Olanzapine may be considered if sexual dysfunction is judged to be secondary to hyperprolactinaemia. Hyperprolactinaemia is usually not clinically significant with aripiprazole, clozapine, olanzapine, and quetiapine treatment. When changing from other antipsychotic drugs, a reduction in prolactin concentration may increase fertility. Patients should receive an antipsychotic drug for 4–6 weeks before it is deemed ineffective. Prescribing more than one antipsychotic drug at a time should be avoided except in exceptional circumstances (e.g. clozapine augmentation or when changing medication during titration) because of the increased risk of adverse effects such as extrapyramidal symptoms, QT-interval prolongation, and sudden cardiac death. Clozapine is licensed for the treatment of schizophrenia in patients unresponsive to, or intolerant of, other antipsychotic drugs. Clozapine should be introduced if schizophrenia is not controlled despite the sequential use of two or more antipsychotic drugs (one of which should be a second-generation antipsychotic drug), each for at least 6–8 weeks. If symptoms do not respond adequately to an optimised dose of clozapine, plasma-clozapine concentration should be checked before adding a second antipsychotic drug to augment clozapine; allow 8–10 weeks’ treatment to assess response. Patients must be registered with a clozapine patient monitoring service. Monitoring Full blood count, urea and electrolytes, and liver function test monitoring is required at the start of therapy with antipsychotic drugs, and then annually thereafter. Blood lipids and weight should be measured at baseline, at 3 months (weight should be measured at frequent intervals during the first 3 months), and then yearly. Fasting blood glucose should be measured at baseline, at 4–6 months, and then yearly. Before initiating antipsychotic drugs, an ECG may be required, particularly if physical examination identifies cardiovascular risk factors, if there is a personal history of cardiovascular disease, or if the patient is being admitted as an inpatient. Blood pressure monitoring is advised before starting therapy and frequently during dose titration of antipsychotic drugs. Other uses Some antipsychotic drugs can be used for the treatment of nausea and vomiting, choreas, and motor tics. Chlorpromazine hydrochloride p. 402 and haloperidol p. 404 can be used for intractable hiccup. Benperidol p. 398 is used in deviant antisocial sexual behaviour but its value is not established. Psychomotor agitation should be investigated for an underlying cause; it can be managed with low doses of chlorpromazine hydrochloride or haloperidol used for short periods. Antipsychotic drugs can be used with caution for the short-term treatment of severe agitation and restlessness in the elderly. Dosage After an initial period of stabilisation, in most patients, the total daily oral dose can be given as a single dose. The Royal College of Psychiatrists has published advice on doses of antipsychotic drugs above BNF upper limit. Antipsychotic depot injections Long-acting depot injections are used for maintenance therapy especially when compliance with oral treatment is unreliable. However, depot injections of conventional Nervous system antipsychotics may give rise to a higher incidence of extrapyramidal reactions than oral preparations; extrapyramidal reactions occur less frequently with second- generation antipsychotic depot preparations, such as risperidone p. 421 and olanzapine embonate p. 422. Choice There is no clear-cut division in the use of the conventional antipsychotics, but zuclopenthixol p. 409 may be suitable for the treatment of agitated or aggressive patients whereas flupentixol decanoate p. 410 can cause over-excitement in such patients. Zuclopenthixol decanoate p. 412 may be more effective in preventing relapses than other conventional antipsychotic depot preparations. The incidence of extrapyramidal reactions is similar for the conventional antipsychotics. Dosage Individual responses to neuroleptic drugs are variable and to achieve optimum effect, dosage and dosage interval must be titrated according to the patient’s response. ANTIPSYCHOTICS Antipsychotic drugs f
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There is a high risk of relapse if medication is stopped after 1–2 years. Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse. Patients should be monitored for 2 years after withdrawal of antipsychotic medication for signs and symptoms of relapse.
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As photosensitisation may occur with higher dosages, patients should avoid direct sunlight. Driving and skilled tasks Drowsiness may affect performance of skilled tasks (e.g. driving or operating machinery), especially at start of treatment; effects of alcohol are enhanced. ANTIPSYCHOTICS › FIRST-GENERATION eiiii F 401
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0.25–1.5 mg daily in divided doses, adjusted
First-line fragment. Read the complete Indications and Dose section above.
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