Drug review Psychosis
Psychoses: current approaches to drug management Martin Livingston MD, FRCPsych Skyline Imaging Ltd
Antipsychotic drugs are a key element in the management of psychosis, usually supported by psychosocial treatments. Our Drug review discusses the properties and uses of the wide range of antipsychotics currently available, followed by sources of further information and a review of prescription data. he ICD10 psychiatric diagnostic system1 sets out criteria for diagnosing the different psychotic illnesses. These include schizophrenia, delusional disorders, severe mood (affective) disorders, and organic psychoses such as dementia and delirium.
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Psychotic illnesses involve impairment of insight and the experience of abnormal mental state features such as delusions, hallucinations and disturbance in the area of semantics often called formal thought disorder. Substance misuse is widespread and distinguishing between a primar y psychosis and a drug-induced illness is often difficult. The difficulty is compounded by co-morbid cases where the substance misuse and the primary psychosis co-exist. In purely drug-induced psychoses the psychotic phenomena usually respond rapidly to withdrawal of the substance that has provoked the psychosis. In delusional disorder, and in the organic psychoses, persecutory delusional beliefs are common, sometimes accompanied by hallucinations, which are of a related theme. In organic psychoses such as dementia, cognitive Prescriber 5 September 2008
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impairment is the most prominent feature. In severe mood disorders, delusions or hallucinations may occur, which may be understood on the basis of the prevailing mental state, eg delusions of poverty in depression or grandiosity in mania. In schizophrenia the mental state abnormalities are wider ranging, often including thought process disorder, chronic or transient mood disturbance, impaired volition and cognitive impairments (see Table 1). Multidisciplinary treatment programmes
The cornerstone of treatment in psychosis, especially where there are positive symptoms such as delusions and hallucinations, is antipsychotic medication. This is usually supplemented by psychosocial treatments organised by multidisciplinary community mental health teams (CMHTs). The teams involve a partnership between GP and specialist medical care, social work and the independent sector. An important task for the CMHT is to ensure that those with severe, insight-impairing mental illness do not slip through the net of care. In the care programme approach, all agencies that are involved with the patient are obliged to meet to set out and manage a care plan with the patient and his or her carer, enabling the lines of communication to be maintained between all the services involved. In addition, many centres have now evolved an integrated care pathway (ICP) for the management of disorders such as schizophrenia. The ICP approach ensures that everyone with a specific diagnosis receives an appropriate care package, which fits together all the necessary elements of the treatment. Early intervention in psychosis
Following the experience of experimental services in the USA and Australia, the government has now invested heavily in setting up special services to treat young people as soon as early signs of psychosis are detected. Innovative clinics have been established in places more acceptable to young people, such as shopping centres and schools. Early inter vention strategies are based on the observation that increasing duration of untreated psychosis was linked with poorer response to treatment and outcome. Lower doses of medication are usually effective and these are coupled with an intensive psychological input. Problems lie in distinguishing between psychotic and nonpsychotic symptoms at this stage and then recruiting the young person to a treatment regimen. Furthermore, there is a risk that some young people who will not go on to develop a frank psychotic illness www.prescriber.co.uk
will nevertheless receive unnecessary, prolonged treatment with antipsychotic medication. Choice of antipsychotic
There is a wide choice of antipsychotic drugs currently available. A major problem is nonadherence to the treatment regimen, often requiring careful monitoring by doctors and community teams. Higher doses may be needed in an acute episode, later to be reduced in the maintenance phase of treatment. Newer, second-generation antipsychotic drugs are less likely to cause movement disorder, and are termed atypical for that reason.2 Sulpiride is an example of an older drug that is less likely to cause movement disorder. Clozapine is the only medication with proven efficacy in treatment-resistant schizophrenia (see Case history 1).3 It too is less likely to induce movement disorder. It is useful not only in treatment-resistant cases but also in patients who have intolerable movement disorder side-effects. Clozapine may only be prescribed under specialist direction. Route of administration and different formulations Antipsychotic medication is administered by the oral or intramuscular route. The intramuscular route is useful when a patient is acutely disturbed. Syrup preparations, eg chlorpromazine and risperidone, are Positive symptoms • delusions • hallucinations • thought disorder Negative symptoms • social withdrawal • lack of volition • poverty of thought • difficulty with abstract thinking • anhedonia Affective symptoms • unstable mood • depression • irritable, disinhibited and mood elevation Cognitive impairments • impaired attention • impaired information processing • impaired verbal fluency • inability to shift construct Table 1. Symptom complexes in schizophrenia Prescriber 5 September 2008
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• assess clinically, obtain history from informant, admit if risk to self or others, detain if necessary using the mental health legislation • treat acute disturbance with benzodiazepine, eg lorazepam, pending diagnosis • investigate, eg full blood count, urea & electrolytes, liver and thyroid function tests • engage with carer • involve relevant multidisciplinary team, eg if first onset, early intervention team, community psychiatric nurse, occupational therapist, clinical psychologist, social worker, independent sector workers Planning the treatment and care programme Medication • use atypical • conventional antipsychotic may be suitable if previously stable on such and relapse due to nonadherence • continue lorazepam if sedation required for 2-3 weeks maximum • if fails to respond to 2 different classes of antipsychotic, consider referral for trial of clozapine • continue antipsychotics as maintenance therapy in most cases
Social • share information with carer, offer support and involvement in care plan • is there a co-morbid substance misuse problem? • are patient and relatives claiming appropriate benefits? • community care needs assessment, social work involvement • is supported accommodation required? • is patient homeless? • assess daily living and job skills involving relevant agencies
Psychological • is there mood dysfunction, either as a feature of the primary illness or due to co-morbid mood disorder? • cognitive behaviour therapy may be useful as adjunctive treatment in delusions and hallucinations • teaching motivational strategies • is there a prodromal pattern predictive of relapse (‘relapse signature’)? • formulate risk management strategy if there is risk of self-harm or aggression
Table 2. Assessment, investigation and care planning in psychosis
also rapid acting. Intramuscular preparations administered at intervals from one week to a month, socalled depots, are useful in the long-term management of patients who have schizophrenia, a chronic paranoid illness, or bipolar disorder with frequent manic relapse. Because the degree of adherence to the treatment is known, depots can assist in achieving a lower, more stable dosage regimen. Consent should be obtained from the patient to administer depots, or indeed any treatment. If this is unavailable and/or the patient lacks the insight to understand what is involved, then compulsory treatment measures may have to be used involving the mental health legislation. The legislation varies with the jurisdiction in which the patient is being treated within the UK. New legislation was enacted in Scotland in 2003, and in England and Wales consultations continue on legislative proposals for mental health. Depots are rather inflexible in situations where rapid dose adjustment is required, eg acute, florid illness, or where there is a need to keep doses very low and respond rapidly to side-effects, as when treating the very elderly. Conventional depots are antipsychotic drugs esterified with long-chain fatty acids (decanoate or enanthate) and then dissolved in an oily vehicle. They are administered by a Z-tracking technique, to 32
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prevent back tracking and leakage of the injection solution, into a deep intramuscular site in the upper outer quadrant of the buttock. One of the atypical drugs, risperidone (Risperdal Consta), is also available as a long-acting injectable. The formulation is different from conventional depots: the drug is attached to a microsphere polymer, which slowly dissolves to release the antipsychotic molecule. Because of a delay of several weeks in releasing the active agent, additional oral antipsychotic cover and clinical supervision are required during this period of time at the start of treatment. Other new orodispersible formulations are available including oral preparations of olanzapine (Zyprexa Velotab) and risperidone (Risperdal Quicklet) that make it difficult to remove the tablet once it is placed in the mouth. These compounds are helpful in assisting adherence to treatment in situations where medication is supervised, for example in day units or residential facilities. Paliperidone (Invega), a metabolite of risperidone, is a newly available second-generation antipsychotic in a novel formulation. It provides for extended release of the medication by means of an osmotic technology enabling consistent drug delivery on the basis of a once-daily dose. www.prescriber.co.uk
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Place of the atypicals Guidelines have been issued by the National Institute for Health and Clinical Excellence (NICE) on the use of antipsychotics, which have also been broadly accepted by the equivalent Scottish regulatory authority. NICE recommends that atypicals be selected for patients in a first episode (see Case history 2) of psychosis, because of the high risk of movement disorder in those receiving antipsychotics for the first time. NICE also advises that atypicals may be suitable for those who are acutely unwell or experiencing movement disorder on typicals (see Case history 3). It is not necessary to change all antipsychotic prescriptions to atypicals, especially if the patient is stable and has few side-effects. In the treatment of schizophrenia, positive psychotic symptoms are more responsive than negative to drug treatment. Amisulpride and clozapine have been advocated for negative symptoms on the basis of clinical trials.4 A balanced view about the place of atypicals is beginning to emerge with increased experience of their use. Early claims of superiority in acute treatment of either positive or negative symptom complexes in schizophrenia are open to challenge.5 Some of the apparent superiority may be due to comparing atypicals with poorly tolerated high doses of haloperidol. Even the claim that atypicals induce less movement disorder has been disputed6 in a meta-analysis of studies comparing the atypicals with low-potency conventional drugs like chlorpromazine, which are less likely to cause movement disorder than haloperidol. Over the course of one year, in a randomised controlled trial of different classes of antipsychotic drugs, there was no disadvantage in terms of quality of life or associated increased costs of care for patients on first-generation drugs compared with those on the newer drugs.7 There is still some uncertainty about atypical dosing schedules, which has resulted in changing recommendations for the use of quetiapine (Seroquel) and risperidone. There have been attempts to sort out concerns about dosing and deal with clinicians’ anxieties when changing from one antipsychotic to another by carrying out so-called drug-switching studies. The atypicals are not free of potentially harmful side-effects. Some patients have developed the metabolic syndrome and maturity-onset diabetes following significant weight gain on atypicals such as olanzapine and clozapine. Doctors who are monitoring patients on longer-term treatment with antipsychotics need to be aware of this problem and monitor blood lipids and glucose at regular intervals. On the positive side, a recent trial showed that oral www.prescriber.co.uk
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risperidone was superior to haloperidol in relapse prevention,8 a finding that awaits replication with other atypicals. In clinical practice, movement disorder is less evident on the new atypicals, and they are usually better tolerated by patients. New indications are developing including use of the atypicals in bipolar disorder to stabilise mood (see Case histor y 4) and to prevent relapse. Aripiprazole (Abilify), olanzapine, quetiapine and risperidone all now have a licence for the treatment of acute mania. Patients and their relatives, informed by therapeutic staff, support groups, the internet and other media, frequently demand treatment with atypical antipsychotics in preference to conventional drugs and there is no doubt that their use is on the increase. Mechanism of action Dopamine is involved in the pathological process of psychosis. All antipsychotic drugs have some capacity to block postsynaptic D2 receptor sites in the brain. The more potent the D2 blockade, the lower the dose of the antipsychotic drug required to treat schizophrenia, or indeed any of the psychoses. Haloperidol, which is a potent D2 blocker, is used acutely in doses of 20mg or less per day, whereas the usual dose range of chlorpromazine, a far weaker D2 blocker, is 200Case history 1: Treatment resistance John (21) was seen by the early intervention in psychosis team when he was persuaded by his family that he needed help. Despite a promising start to a college course his academic performance had begun to decline about 8 months ago. He seemed distracted, and at times hostile. He had opted out of his usual interests and reluctantly, on probing, admitted that he was hearing voices making insulting remarks about him. Following detailed multidisciplinary assessment he had been diagnosed with schizophrenia. Despite support, psychological treatment targeted at his delusional beliefs, and treatment with aripiprazole, he had become more withdrawn and seemed to be responding to his hallucinations. His community psychiatric nurse wondered whether he was adherent to medication, in view of his suspiciousness. Reluctantly he agreed to accept a long-acting injectable antipsychotic medication, risperidone. The dose over the next 3 months was increased to a maximum of 50mg per fortnight im. He remained aloof although less hostile, but still admitted to hearing voices. Following discussion with John and his family, he agreed to try clozapine. The dose was gradually increased to 450mg per day with good effect. He has so far been unable to resume his college course but began to take an interest again in his hobbies and relationships. Self-care improved and the delusions and hallucinations became much less overt. John agreed to become involved in a football team organised by his community psychiatric nurse to help him lose weight he had gained while on treatment.
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1000mg per day for acutely ill people. Recent neuroimaging studies have demonstrated that the dopamine system is hyperactive in acute schizophrenia, although it is not clear whether this is the primary pathological process.9 Evidence is accumulating of involvement of glutamate pathways in schizophrenia.10 Newer atypical antipsychotics may be responsible for less extrapyramidal symptoms (EPS), a reduced risk of tardive dyskinesia (TD) and lack of prolactin elevation due to looser binding of the drug to the D2 receptor site.11 This observation also implies that nonadherent patients may be better off treated with a more tightly receptor-bound conventional drug, minimising the risk of relapse from intermittent missed doses. This argument may also be used to advocate for conventional depot antipsychotic treatment for those who are invariably nonadherent. Antipsychotics work in all psychoses, not just schizophrenia, and therefore dopamine may be relevant to the development of delusions and hallucinations in psychotic disorders in general (see Case history 5). Antagonism of 5HT2, an important part of the profile of activity of atypicals, is also present in some of the typical drugs, eg chlorpromazine. This neurotransmitter action appears to reduce the incidence of movement disorder and to improve mood. Clozapine, a treatment for nonresponders to other antipsychotics, antagonises a wide range of neurotransmitters, apart from D2; of these D3, D4, 5HT2, 5HT6 and 5HT7 may be relevant to schizophrenia and other psychoses. This knowledge has stimulated research into drugs that mimic some or all of these actions in the hope of finding a safer but more effective antipsychotic. A recent suggestion is that potent alpha2a- and alpha2c-adrenergic blockade added to the dopamine blockade is the key activity to clozapine’s superior efficacy. 12 The hope is that such research will also provide more information on the causes of schizophrenia and other psychoses. Avoiding side-effects Antipsychotic side-effects are listed in Table 3 together with their pharmacological basis. Antipsychotics lower the seizure threshold, especially clozapine. This important side-effect limits the use of higher doses of clozapine, as well as excessive and often incapacitating sedation. The neuroleptic malignant syndrome (NMS) is a rare, but potentially fatal, complication of antipsychotics and other dopamine-blocking drugs such as metoclopramide. The clinical picture is of a fluctuatwww.prescriber.co.uk
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Case history 2: First episode of psychosis Mary (19) had always been shy and socially awkward, despite having an engaging manner. She had a small circle of close friends and enjoyed reading and listening to music. Her mother thought she had become depressed, noticing she was even quieter, seemed vague and distracted, and was off her food. She seemed quite suspicious at times, questioning whether family members had been talking about her in a negative way. She also seemed unusually concerned about her personal hygiene, showering several times a day. At one point she asked her sister if she had developed an unpleasant body odour. Mary plucked up the courage to attend her GP who asked the early intervention in psychosis team to visit. She was seen by a nurse and consultant psychiatrist at home, who felt she was psychotically unwell but a more specific diagnosis was not yet possible. There was a family history of depression: her grandmother had been admitted to a psychiatric unit 12 years ago for this disorder, and also a cousin had suffered from a paranoid illness. Mary agreed to start treatment with low-dose risperidone 1mg per day and to participate in the team’s comprehensive programme for young people with first-onset psychosis.
ing level of consciousness, severe rigidity and hyperpyrexia, and the biochemistry reveals a grossly elevated creatine phosphokinase (CPK). Frequent changes of dopamine-blocking drugs increase the risk, and leave the prescriber in doubt as to which drug caused the problem. Care has to be taken in particular with refractor y patients, newly diagnosed with schizophrenia, who may receive two different antipsychotics consecutively followed by clozapine within a space of 12-16 weeks. The treatment of NMS consists of withdrawing the drug, cooling the patient and possibly administering bromocriptine or dantrolene sodium (Dantrium). It is preferable to use a different antipsychotic if continuing drug treatment for the psychosis after an episode of NMS, but cautious reintroduction of the offending drug has been tried successfully. This is a critical issue when the patient only responds to clozapine and has developed NMS on that drug. Side-effects, rather than putative differences in efficacy, are the usual reason for selection of an antipsychotic. It is important to keep doses as low as possible to minimise side-effects. This can only be achieved by regular review to pre-empt relapse, a process that should involve medical staff and is often shared by GP www.prescriber.co.uk
and specialist alike. Simple drug regimens are usually best and help the patient and carers to ensure adherence to the prescription, ideally one drug administered by one route, especially in longer-term maintenance therapy. Despite a past enthusiasm for high doses, there is little evidence that these are more effective. Guidelines are available on the use of high doses of neuroleptics.13 Patients who are insight impaired may nonetheless give accurate information on their drug side-effects. Listening to the patient carefully obviously helps to establish a sound therapeutic alliance to promote treatment adherence and to avoid more severe problems. At the same time, when listening to complaints of side-effects, it is useful to remember that patients who are on inert placebo in drug trials frequently complain of nonspecific side-effects such as headaches, sedation, bowel upset and even dr y mouth and blurred vision, sometimes as often as those receiving active drug. Postural hypotension may be avoided by using haloperidol, olanzapine and quetiapine. Postural hypotension is especially troublesome in older people, in whom it can be incapacitating, even with quite small doses of drug. If it is essential to avoid movement disorder eg in patients with psychoses associated with organic cerebral impairment and Parkinson’s disorder, and those who have developed movement disorder before on other antipsychotics, sulpiride and the newer atypicals such as quetiapine, risperidone and olanzapine are good choices. In older people, it is better to select a drug that has little or no anticholinergic action as this may cause or exacerbate cognitive impairment. The choice of atypical for older people with dementia is now limited as olanzapine and risperidone have been associated with an increased incidence of stroke in these patients. The CSM has advised that neither drug should be used to treat behavioural disturbance in dementia. If risperidone is selected for use in acutely psychotic older people with dementia, it should be used short term under specialist advice, and care should be exercised with all patients who have had a cardiovascular event or significant risk factors for such. Amisulpride and aripiprazole are useful options. Haloperidol, risperidone and sulpiride tend to be less sedating, an asset in some patients but a drawback in others. Weight gain is a feature of all antipsychotic drug treatment. The causes are reduced activity due to sedation, diet and pharmacological activity at neurotransmitter sites implicated in the control of human appetite and glucose metabolism. Weight gain is espePrescriber 5 September 2008
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cially problematic with drugs such as chlorpromazine, olanzapine and clozapine, which possess wideranging neurotransmitter effects. Antipsychotics such as these that block H1 receptors are the most likely to provoke weight gain. GPs now have targets with respect to monitoring for cardiovascular and metabolic syndrome risk factors, and it is important to be aware that patients on some antipsychotics are at higher risk of these disorders. Some psychiatric clinics now offer advice on diet and exercise, together with waist measurement and regular weighing for all patients on antipsychotics. Heavy cigarette (and cannabis) smoking and poor diet are common in people who have chronic, severe mental illness. Aripiprazole, quetiapine and clozapine do not elevate prolactin levels. These drugs are useful for patients who complain of galactorrhoea or amenorrhoea. A tragic but fortunately rare event occurring with antipsychotics is sudden death. This occurs more frequently on antipsychotics that have an impact on cardiac rate or rhythm, eg chlorpromazine or thioridazine, due to prolongation of the QT interval; the prescription of thioridazine has been restricted because of this problem. The compulsory administration of intramuscular medication where a patient is being restrained seems to increase the risk, and all units involved in treating mentally ill patients need to have clear guidelines on restraint and ensure that staff are adequately trained in the correct procedures. Blood monitoring for patients on clozapine Although all of the antipsychotics have the potential to cause blood dyscrasias, clinically significant problems are rare, except with clozapine where the incidence of reversible neutropenia is 3 per cent and of agranulocytosis 0.6 per cent in the UK. Clozapine must be dispensed from registered hospital and community pharmacies. Treatment is usually initiated during inpatient admission. Patients may, of course, live in the community on clozapine, if fit for discharge; this is often a key treatment goal where clozapine is given to a person who has spent prolonged periods in hospital. Clozapine has also had a beneficial impact on previously treatment-resistant patients who are in forensic settings where treatment can be supervised closely. Blood testing of clozapine patients for changes in the white cell count is mandator y. The full blood count is measured weekly for 18 weeks, then fortnightly and, after a year, monthly. The medication is only supplied to the patient after a haematology screen shows white cells within a satisfactory range. Drug-drug interactions 40
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Case history 3: Severe movement disorder Paul (36) had been receiving quetiapine 600mg per day for about 8 years. It had successfully maintained him in remission from his schizophrenic illness and there was no evidence of movement disorder. He had presented to accident and emergency after being injured in a brawl while drinking after attending a football match at which his team had lost. Unfortunately he had sustained fractures involving his left clavicle and acromioclavicular joint requiring open reduction and internal fixation and was admitted for several days to the orthopaedic unit. The following night he became agitated and restless, shouting out and pulling at his drip. He was sweating and tremulous and there was concern he was in delirium tremens. The trainee doctor called to deal with this administered initially 5mg haloperidol im, which was repeated twice over the next few days. The agitation began to settle, as did the sweating, but he became more tremulous and complained of intensely painful neck stiffness. On examination his neck was hyperextended and rotated. On taking a more detailed history he said something similar had occurred in the past when given metoclopramide for vomiting. A diagnosis of acute dystonia was made, haloperidol stopped and the chlordiazepoxide detoxification regimen was increased. The dystonia resolved rapidly. A warning was placed on Paul’s case notes regarding his susceptibility to dystonia with dopamine-blocking drugs, and advising that atypical antipsychotics be used where possible.
There are few clinically significant drug-drug interactions with the antipsychotic drugs. Carbamazepine should not be given with clozapine: both are potentially myelosuppressive. The relatively rare risk of ventricular arrhythmias and sudden death on antipsychotics is increased if such drugs are prescribed concurrently with amiodarone and disopyramide. When given with tricyclic antidepressants (TCAs), antipsychotics augment anticholinergic and alpha1adrenergic blockade, increasing the risk of cardiac rhythm problems. This combination also enhances sedation due to H1 antagonism if this effect is present in both drugs. Even if tricyclics are less frequently used in depression, where an SSRI is usually the first-line drug, they are often used in small doses for relief of chronic pain. Antipsychotics with anticholinergic activity should also be avoided in patients on antidementia acetylcholinesterase inhibitors. Such a combination could effectively neutralise the acetylcholinewww.prescriber.co.uk
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enhancing potential of drugs such as donepezil (Aricept). The manufacturer of artemether with lumefantrine (Riamet), an antimalarial preparation, advises against giving this preparation to those already taking antipsychotics and other potentially myelosuppressive drugs due to an increased risk of toxicity. Ritonavir (Norvir), an antiviral agent, increases the plasma concentration of clozapine, pimozide (Orap) and possibly other antipsychotics. Patients on antiparkinsonian drugs such as levodopa may find that there is a reduction in effect due to D2 blockade by antipsychotics in the basal ganglia. The treatment of psychotic symptoms in patients with idiopathic parkinsonism is difficult: it usually involves a compromise between aggravating the movement disorder with the antipsychotic drug or the psychosis with levodopa. Quetiapine and aripiprazole are good choices in this indication. Antacids reduce the absorption of phenothiazines such as chlorpromazine. Initiating treatment
Diagnostic confirmation of a psychosis is the first step as it is difficult to discontinue antipsychotics where the diagnosis later seems in doubt. Substance misuse Case history 4: Bipolar disorder, manic phase Colin is a middle-aged man who has twice been hospitalised for severe depression and some years ago had a 2-day period of being overtalkative, somewhat irritable and grandiose and did not sleep. This brief period of elevated mood resolved without intervention and he was therefore being treated as suffering from unipolar depression, maintained on lofepramine 210mg per day. Three weeks ago, despite being unemployed, he bought a new sports car on hire purchase. His wife noticed he was speaking in a rapid, pressured manner and again he had sleep dysfunction. Always keen on DIY he had started, but failed to complete, several projects and had left tools and debris scattered around his home, a contrast with his usual neat and tidy approach. When challenged about the number of projects on the go, he said that he had plenty of energy and would complete all of the projects quite soon. His speech seemed to contain a number of puns and rhymes. Colin’s wife persuaded him to accept referral to his local mental health resource centre where the diagnosis was revised to that of a bipolar illness. Treatment was initiated with olanzapine 5mg per day, increasing to 15mg per day in increments. Lofepramine was withdrawn in case this had precipitated the mania. Admission was avoided with daily home input by the crisis team. His treating psychiatrist decided to postpone consideration of longerterm mood stabilisation until the acute episode had settled, but expected that a combination of olanzapine and an SSRI such as fluoxetine might be good choices, since lithium was contraindicated due to Colin’s psoriasis.
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may cause patients to become psychotic, and the psychosis may resolve quite rapidly on withdrawal of the offending drug. A brief drug-free period, if clinically feasible, is helpful in reaching the diagnosis. An individual facing intense stress may present with what at first sight seems to be psychotic symptoms in order to gain admission to hospital. This is an increasing problem with asylum seekers who are threatened with deportation and results in difficult clinical, and indeed ethical, judgements. Patients who have severe personality disorders, especially if there is a history of sexual abuse, severe physical and emotional deprivation in childhood, or bereavement, sometimes talk of hearing voices. A careful history reveals these are usually internal experiences, generally most apparent during periods of altered consciousness such as falling asleep or wakening, and involve themes directly related to the abuse or loss. The voice or voices are recognisable as a person with whom the patient has had a difficult and often ambivalent relationship, eg an abusing father. This type of presentation is also found in patients of low intelligence. It is usually unrewarding to treat such patients with antipsychotics and some receive high doses of such drugs with limited benefit. In psychosis, the false perception is usually described as an experience external to the self, although in the case of auditory hallucinations that experience may retreat to the internal world as the phenomena respond to treatment. Once a diagnosis of a psychotic illness has been made, begin treatment with a low dose of the antipsychotic. Patients tend to remain long term on the dose levels at which they appear to have responded, and if they relapse the dose is then increased again. Psychotic phenomena do not respond immediately: there is usually a delay of several weeks before the effective dose brings about remission. It is difficult to judge what that dose may be if the dose escalation has been over-rapid. The practicalities of inpatient and community treatment do not always allow for such a gradual approach and a benzodiazepine such as diazepam or lorazepam may be added for urgent sedation. The addition of a benzodiazepine is more often necessary with nonsedating antipsychotics such as aripiprazole. This approach minimises movement disorder and other antipsychotic drug side-effects, but it is essential to withdraw benzodiazepines as soon as possible to avoid dependency, especially as many patients with psychosis have co-morbid alcohol and substance misuse disorders. PET (positron emission tomography) imaging www.prescriber.co.uk
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work suggests that psychosis responds when around 65 per cent of D2 receptors are blocked in the brain, a level attained with relatively modest doses of conventional drugs, eg 200mg chlorpromazine. This is considerably less than is customarily used in acute psychosis but nearer to the doses used in maintenance therapy. We could be overtreating some patients with antipsychotics, as movement disorder seems to develop at around 75-80 per cent D2 blockade. Most patients with schizophrenia, or other enduring psychosis, should remain on their medication indefinitely. However, even in the carefully managed scenario of a clinical trial more than 70 per cent of patients stopped their oral antipsychotic medication within 18 months.14 The atypicals are increasingly prescribed long term too, as add-on therapy or secondline drugs in the maintenance phase of bipolar disorder to prevent relapse. Some patients whose psychosis is linked to substance misuse recover rapidly in an environment free of nonprescribed drugs, a situation that is not always the case in psychiatric units, and do not need antipsychotics (see Case history 6).
Side-effect(s)
Mechanism
akathisia, dystonia, parkinsonism, tardive dyskinesia
D2 blockade in nigrostriatal pathway
dry mouth, blurred vision, urinary hesitancy, constipation
muscarinic M1 blockade
sedation
histamine H1 blockade
postural hypotension
alpha1-adrenergic blockade
weight gain
?DA, 5HT, H1 and NA blockade altered glucose metabolism
galactorrhoea, amenorrhoea
D2 blockade causing prolactin increase
Table 3. Antipsychotic side-effects and their mechanisms
Conclusions Case history 5: Psychosis in dementia Jane’s husband, whom she had married 58 years ago, had died over a year ago. Her daughter Sandra visited her twice a week. She had noticed that her 83-year-old mother, who had been very forgetful for several years and was now taking donepezil, had great difficulty in coming to terms with the loss. At first this has been evident in crying and sobbing and saying how much she missed her husband. In the last few weeks, however, Jane had declared that he had returned to her and she had begun to put out meals for him, make up his bed and talk to him. When Sandra tried to challenge her mother, saying gently that he had died, Jane had reacted angrily replying, ‘He’ll be back from work soon and then you will see’. The GP who visited at Sandra’s request found a rather hostile elderly lady, whose self-care had deteriorated. She refused to co-operate with the Mini Mental State Examination test but history-taking revealed that her memory for more recent information had deteriorated and that she was disorientated for time and place. Despite attending to some aspects of the domestic routine in her house, Jane insisted that she was in a friend’s house and had left her husband at home. Jane reacted again with anger to the GP’s attempt to return to the subject of the death of her husband. Following discussion with Jane and her daughter, the GP recommended adding a small dose of the antipsychotic quetiapine, 25mg, to treat the delusions and hallucinations. The GP hoped this would not aggravate the mild parkinsonian tremor that Jane had had for some years now but was not as yet being treated. Sandra thought that one of Jane’s carers who called daily might be able to persuade her to take this additional medication as she had a very good relationship with her mother. The GP offered to review the situation in 2 weeks and inform the psychiatrist who was prescribing the donepezil.
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Antipsychotic drugs are a key element in treating psychosis. The choice of drug depends on the individual patient’s clinical needs. Atypical antipsychotics are increasingly selected as they are often better tolerated. Successful treatment with antipsychotics for patients with enduring illnesses is generally the first stage in a comprehensive management plan, which includes psychosocial treatments and supports organised by a multidisciplinary mental health team. References
1. World Health Organization. The ICD-10 classification of mental and behavioural disorders. Clinical descriptions and diagnostic guidelines. Geneva: WHO, 1992. 2. Barnes TR, McPhillips MA. Novel antipsychotics, extrapyramidal side effects and tardive dykinesia. Int Clin Psychopharmacol 1998;suppl 3:S49-57. 3. Kane J, Honigfeld G, Singer J, et al. Clozapine for treatment-resistant schizophrenia. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988;45(9):789-96. 4. King DJ. Drug treatment of the negative symptoms of schizophrenia. Eur Neuropsychopharmacol 1998;8:33-42. 5. Geddes J, Freemantle N, Harrison P, et al, for the National Schizophrenia Guideline Development Group. Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ 2000;321:1371-6. 6. Leucht S, Wahbeck K, Hamann J, et al. New generation antipsychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet 2003;361:1581-9. 7. Jones PB, Barnes TRE, Davies L, et al. Randomised conwww.prescriber.co.uk
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Case history 6: Drug-induced psychosis Police were called to Graham’s house after neighbours complained of the noise and sounds of breaking furniture. On arrival, the 22 year old was shouting that he could hear his neighbours calling him a paedophile. He was frightened and agitated. The house was in a chaotic state, with items of household furnishings and a new flat-screen television broken. He agreed to come to the psychiatric unit for assessment but then refused to stay. Graham was detained on the grounds that he had a psychotic mental state with auditory hallucinations and persecutory delusions, was at risk of self-harm, was refusing treatment and was insightless. It was only possible to take a fuller history the following morning. He said he had been using amphetamines, bought ‘on the street’, for about a week much more heavily than usual and had not slept in 4 days. He had tried to control the voices by taking more amphetamine and had stopped his medication, amisulpride, which he felt was not helping. He said he had been under some pressure due to an impending court case involving a criminal charge. On admission he was prescribed lorazepam to assist with sleep and to sedate him, pending a decision about whether to recommence his antipsychotic, change to another oral preparation or opt for a long-acting depot such as Risperdal Consta because of nonadherence to oral regimens. Graham rapidly settled over a 48-hour period. He refused the injectable preparation but agreed to recommence amisulpride 200mg twice daily and to attempt to re-engage with the community addiction team on discharge.
trolled trial of the effect on quality of life of second-vs firstgeneration antipsychotic drugs in schizophrenia. Cost utility of the latest antipsychotic drugs in schizophrenia study (CUtLASS 1). Arch Gen Psychiatry 2006;63:1079-87. 8.Csernansky JG, Mahmoud R, Brenner R for the Risperidone-USA-79 Study Group. A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med 2002;346:16-22. 9. Laruelle M, Abi-Dargham A, Gil R, et al. Increased dopamine transmission in schizophrenia: relationship to illness phases. Biol Psychiatry 1999;46(1):56-72. 10. Krivoy A, Fischel T, Weizman A. The possible involvement of metabotropic glutamate receptors in schizophrenia. Eur Neuropsychopharmacol 2008;18(6):395-405. 11. Kapur S, Seeman P. Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics: a new hypothesis? Am J Psychiatry 2001;158:360-9. 12. Sokoloff P. Focus on clozapine: a new explanation for its atypical character. Int J Neuropsychopharmacol 2005;8(3):311-3. 13. Thompson C. The use of high-dose antipsychotic medication. Br J Psychiatry 1994;164:448-58. 14. Lieberman JA, Stroop TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353(12):1209-23.
Dr Livingston is consultant psychiatrist at The Southern General Hospital, Glasgow
Resources Groups and organisations MIND, 15-19 Broadway, London E15 4BQ. Tel: 0845 766 0163 (infoline); website: www.mind.org.uk – offers information about local services, campaigns and publications. Rethink (formerly the National Schizophrenia Fellowship) Head office, 5th Floor, Royal London House, 22-25 Finsbury Square, London EC2A 1DX. Tel: 0845 456 0455; e-mail:
[email protected]; National Advice Line: 020 8974 6814; website: www.rethink.org. primary care Mental Health & Education (priMHE), Unit 6, 2a Laurel Avenue, Twickenham, Middlesex TW1 4JA. Tel: 020 8891 6593; website: www. primhe.org. Royal College of Psychiatrists, 17 Belgrave Square, London SW1X 8PG. Tel: 020 7235 2351; website: www.rcpsych.ac.uk – provides many materials for both patients and healthcare professionals including patient information leaflets, posters and books. 46
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Schizophrenia Association of Great Britain, Br yn Hyfr yd, The Crescent, Bangor, Gwynedd LL57 2AG. Tel: 01248 354048; e-mail:
[email protected]. Mental Health Foundation, London office, 9th Floor, Sea Containers House, 20 Upper Ground, London SE1 9QB. Tel: 020 7803 1100; website: www.mental health.org.uk; e-mail: mhf@mhf. org.uk. SANE, 1st Floor, Cityside House, 40 Adler Street, London E1 1EE. Tel: 020 7375 1002; website: www.sane.org.uk; SANEline: 0845 767 8000. Useful websites The Cochrane Library: www.cochrane.org. National electronic Library for Mental Health, a virtual branch library of the National electronic Library for Health: www.library.nhs.uk/mentalhealth. NICE guidance on the use of atypical antipsychotics in schizophrenia: www.nice.org.uk:80/Guidance/TA43. www.prescriber.co.uk
