Antipsychotics in the treatment of schizophrenia

Transcription

1 Antipsychotics in the treatment of schizophrenia Caroline Parker MRPharmS, MCMHP In the first of a new series of updated articles on the major psychiatric drug groups, produced in association with the College of Mental Health Pharmacy ( Caroline Parker summarises the use of antipsychotics through a review of the clinical literature. Pharmacology, interactions and side-effects as well as drug choice and information to give to patients are discussed. Schizophrenia is a severe and relapsing illness that may lead to chronic symptoms with incomplete resolution. It has a lifetime incidence of approximately 1 in 100 people, and the prevalence rate for probable psychotic disorder in the past year is 5 per 1000 adults. 1 People with schizophrenia or psychosis may have a range of symptoms characterised by distortions in thinking and perception, and an inappropriate or blunted affect. Symptoms are often described in two groups positive and negative. Positive symptoms include hallucinations such as hearing voices, delusions, or experiencing strange things such as seeing or feeling things that may not be real. People may also feel suspicious or paranoid, have mistaken beliefs or feel that other people can read their thoughts. Negative symptoms are less noticeable than positive symptoms, and include a lack of concentration, Extrapyramidal side-effects (EPSE) consist of: Parkinsonian symptoms: include tremor, rigidity, bradykinesia and stooping gait, which may appear gradually. These may remit if the antipsychotic is withdrawn, and may be suppressed by the administration of antimuscarinics. However, routine co-administration of antimuscarinics is not justified because not all patients are affected. Antimuscarinics are also associated with adverse effects and may unmask or worsen tardive dyskinesia. Acute dystonic reactions (abnormal face and body movements) and dyskinesia: occur more commonly in children or young adults and may appear after only a few doses. These are acute and painful and need immediate treatment with antimuscarinics often in the parenteral form. Akathisia (inner restlessness): 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): usually develops following long-term use of antipsychotics or with high doses, but it may develop on short-term treatment with low doses. It is of particular concern because it may be irreversible on withdrawing therapy and treatment is usually ineffective. However, drug withdrawal at the earliest signs may halt its full development. Box 1. Movement disorders associated with antipsychotics 8 reduced energy and lack of thoughts, consequently some people may become quite inactive and withdrawn from normal everyday activities. Diagnoses are formally made using the ICD-10 classification system. 2 The current evidence generally suggests that the longer the illness is left untreated the poorer the prognosis. 3 Antipsychotics are an essential treatment for most individuals with schizophrenia 4,5 and are considered first-line pharmacotherapy. Antipsychotics can help to treat acute symptoms, and maintain remission from the illness. 5 The main aim of antipsychotic treatment is to prevent acute relapse and to help keep the person well and stable. Antipsychotics are a core treatment in the management of schizophrenia, but they are just one part of the package of care that contributes towards this aim. 5 They are not effective in all cases. This article gives a brief overview of antipsychotics; the non-pharmacological measures that should also be used (social, occupational and psychological) are outside the remit of this article. Evidence base supporting pharmacotherapy Antipsychotics have been in wide use in the UK since the 1950s. Since that time there has been an increasing number of antipsychotics available, in a range of formulations (tablet/capsules, liquids, short-acting injections, intermediate-acting injections, and longacting depot injections). Over time the development of antipsychotics has continued to focus on finding agents of greater efficacy 6 with a lower side-effect burden. 7 Consequently there are now nearly 30 antipsychotics licensed for use in the UK and listed in the current BNF, 8 of which 13 are recommended for use in children. 9 The antipsychotics that were first available were commonly known to cause extrapyramidal movement disorders as a side-effect (EPSE; see Box 1). It was not established until the development of clozapine in the 6 Progress in Neurology and Psychiatry May/June

2 Antipsychotics for schizophrenia z Review 1980s that antipsychotic efficacy could be achieved without inducing EPSE. Thereafter, development of antipsychotics strove to ensure antipsychotic efficacy without EPSE, and without inducing blood dyscrasias such as those that limit the use of clozapine. Antipsychotics developed after clozapine were termed atypical, while the older antipsychotics, which typically caused EPSE, became known as typical anti psychotics. In some literature these two groups of antipsychotics are termed first and second generation antipsychotics. The BNF 8 classifies all antipsychotics as typical or atypical. Although there are no definitive criteria for this classification, 3,7,10 it is generally accepted that when used at therapeutic doses atypical antipsychotics tend not to cause EPSE and tend not to disturb prolactin regulation. Importantly this is not without exception, as some so-called atypical antipsychotics can cause EPSE and disturb the regulation of prolactin even at therapeutic doses, eg risperidone, amisulpride. Therefore these two classifications are better viewed as principles, and it is helpful not to consider antipsychotics as being in two discrete groups, but rather, on a continuum as shown in Figure 1. Pharmacology All current antipsychotics, both typicals and atypicals (with the exception of aripiprazole), antagonise dopamine receptors (D 2 ); this is hypothesised as their main mode of action. 5,8 This is often referred to as the dopamine hypothesis. In addition to antagonism of D 2 receptors, most of the existing antipsychotics also act at a range of other receptors not contributing to their antipsychotic activity, eg other sub-types of dopamine receptors, histamine-1 receptors, cholinergic receptors and alpha-1 receptors. Consequently the pattern of receptor blockade by individual agents leads to pharmacologically predictable side-effects such as sedation (histamine blockade), dry mouth, blurred vision, constipation, urinary retention (cholinergic blockade), postural hypotension, dizziness and syncope (alpha antagonism) (see Table 1). In addition to the core hypothesised mechanism of action, with the exception of amisulpride, the atypical antipsychotics also antagonise serotonergic receptors (5HT 2a ) in a varying but greater degree in proportion to their D 2 antagonism. This is still an area of considerable research, but it is now thought that antipsychotic activity may be related to the ratio of activity at D 2 /5HT 2a receptors, and that glutamate may also be involved. Aripiprazole has been described as a third generation antipsychotic with a unique mode of action. It acts as a potent partial agonist at D 2 dopamine and Oily depots Haloperidol Trifluoperazine Chlorpromazine Sulpiride Zotepine Amisulpride Risperidone = Paliperidone Asenapine Olanzapine Quetiapine Aripiprazole Clozapine Typical Atypical Figure 1. It is helpful not to consider antipsychotics as being in two discrete groups, rather, on a continuum 5-HT 1a serotonin receptors, and as an antagonist at 5-HT 2a serotonin receptors. Despite this postulated mechanism of action, a Cochrane review 11 concluded that aripiprazole was equally effective as typical and atypical antipsychotics. Choice of antipsychotic Despite a wide selection of antipsychotics with different chemical structures, suggested variation in mechanisms of action and safety profiles, there have been a number of studies and meta-analyses in recent years demonstrating that all antipsychotics are of similar efficacy for the treatment of positive symptoms of schizophrenia, with the exception of clozapine (see later). There is no clear advantage of atypical over typical antipsychotics. 5,12-15 However, the treatment of negative symptoms is often poorer than positive symptoms. In recent years, the atypical antipsychotics olanzapine, risperidone and quetiapine have become the most widely prescribed antipsychotics. 16 The choice of antipsychotic should always be informed by a patient s previous response to treatment, past experiences (including side-effects) and preference, as well as any concurrent medical co-morbidity and medication 4,5 (see Table 1). An atypical antipsychotic should be considered for people with an existing diagnosis of schizophrenia who are already prescribed a typical antipsychotic but are experiencing intolerable side-effects, such as EPSE. NICE 4 also encourages prescribers to consider the use of clozapine as early as possible. For example, for patients with an unsatisfactory treatment response to a full trial of two other antipsychotics. Sadly surveys of current practice suggest that its use is commonly withheld, and not given as early as it could be. 17 There is still a role for typical antipsychotics, for example, for patients who have responded well to Progress in Neurology and Psychiatry May/June

3 Drug Effect Sedation Weight EPSE Hyper- Postural Anticho- Formulations Additional on QTc gain prolactin- hypotension# linergic available information / aemia comments Typical antipsychotics (by BNF listing) Chlorpromazine Tablets, liquids Phenothiazine Short-acting injection is not recommended Flupentixol Depot for IM Thioxanthine administration every 1-4 weeks (as decanoate) Fluphenazine Depot for IM Phenothiazine administration every 2-5 weeks (as decanoate) Haloperidol Tablets, liquid, Butyrophenone short-acting injection. Depot for IM administration every 4 weeks (as decanoate) Levomepromazine? Tablets, short- Phenothiazine (methotrimeprazine) acting injection Perphenazine Tablets Phenothiazine Pimozide Tablets Diphenylbutylpiperidine CSM warning 1990 about ECG monitoring requirements Pipotiazine Depot for IM Phenothiazine administration every 4 weeks (as palmitate) Sulpiride Tablets, liquid Substituted benzamide Trifluoperazine? /+ Tablets, liquid Phenothiazine Zuclopenthixol? Depot (as Phenothiazine decanoate) This is the cis isomer of for IM admin clopenthixol, which was every 1-4 weeks. available as a depot Short-acting until1985 IM injection (as acetate, Acuphase), lasting for 3 days Table 1. Overview of adverse reactions of common antipsychotics and their formulations 8,10,13 8 Progress in Neurology and Psychiatry May/June

4 Drug Effect Sedation Weight EPSE Hyper- Postural Anticho- Formulations Additional on QTc gain prolactin- hypotension# linergic available information / aemia comments Atypical antipsychotics (by BNF listing) Amisulpride Tablets, liquid Aripiprazole / Tablets, oro- (aka- dispersible tablets, thisia) liquid, shortacting injection Asenapine +? ? + - Sublingual tablets Only licensed for the treatment of moderate to severe manic episodes. Only 2% bioavailability if swallowed (cf 35% sublingually) 30 Clozapine Tablets For treatment-resistant schizophrenia, mandatory regular FBC tests, and registration with monitoring agency Olanzapine /+ -/+ + Tablets, oro- Risk of post-injection dispersible tablets, syndrome with the short-acting depot, careful injection, depot observation (as embonate) required for 3 hours for IM admin. post-dose every 2 or 4 weeks Paliperidone Tablets, depot Primary active (as palmitate) metabolite of for IM admin. risperidone every 4 weeks Quetiapine Tablets (for twice daily use) and XL tablets (for once daily use) Risperidone Tablets, oro- Injection requires dispersible tablets, refrigeration liquid, long-acting IM injection for administration every 2 weeks EPSE: Extrapyramidal side-effects # this effect is dose related Incidences: +++ High, ++ Moderate, + Low, - Little or minimum,? unknown Table 1. Overview of adverse reactions of common antipsychotics and their formulations (cont.) 8,10,13 10 Progress in Neurology and Psychiatry May/June

5 them, or would prefer them, or who do not tolerate the side-effect profile of some atypical agents. Outside of these circumstances, there are no specific guidelines as to which agent(s) should be used; decisions should be guided by the factors mentioned above. Depot antipsychotics There may be circumstances where oral formulations of antipsychotics may not be suitable, eg for patients who struggle to remember to take medicines regularly and for those with swallowing problems. For such patients a depot intramuscular formulation may be an alternative strategy for maintenance treatment. 18 Some patients also prefer to have a depot as this avoids the daily routine of taking oral medicines. Antipsychotics have been available in depot formulations since the 1960s; there are now a number available (see Table 2) and they are widely used. 19 Despite this increasing range of options in terms of treatment efficacy and overall adverse effects, there is minimal discernable difference between the depot formulations; 20,21 however, there are notable practical differences. 22 Three atypicals and five typical antipsychotics are currently licensed in the UK as long-acting depot formulations for intramuscular injection. The typical formulations are oily injections given between every one to five weeks; the atypical formulations are aqueous suspensions, which are given every two to four weeks (see Table 2). For further reading on depot antipsychotics please refer to a review article in Drugs (2003). 15 Treatment in children Treating prodromal symptoms of schizophrenia is fraught with ethical considerations and has been subject to much debate. Although it is recommended in some guidelines, 5 treating those under 18 years old is explicitly not recommended in the recent NICE guideline on the treatment of schizophrenia in children and young people. 23 Treatment-resistant schizophrenia Following a notable trial in 1988, 6 clozapine was demonstrated to have superior efficacy over other antipsychotics available on positive symptoms of schizo phrenia, in patients with a treatment-resistant illness, defined as a lack of response to two other antipsychotics. Additionally, clozapine was the first antipsychotic to be termed atypical, since it did not typically induce EPSE. 24,25 More recent studies have also confirmed the drug s greater efficacy compared with typical and other atypical antipsychotics; 26,27 it has also been shown to reduce the incidence of suicide in schizophrenia. 28 Despite the greater efficacy, clozapine is not recommended as a first-line antipsychotic, as it can cause neutropenia followed by agranulocytosis, which if left unchecked can be fatal. Consequently it can be used only by healthcare professionals and patients registered with a clozapine monitoring agency, where regular (initially weekly) full blood count tests are mandatory prior to medicine supply. 29 In practice the need for regular blood tests and the restriction of medicine supplies means that this is not always a feasible option for some patients, eg needle-phobic patients. Generic name Formulation Administration (IM) and comments Available since Zuclopenthixol decanoate Oily Gluteal, every one to four weeks 1978 Flupentixol decanoate Oily Gluteal, every one to four weeks 1972 Haloperidol decanoate Oily Gluteal, every four weeks 1982 Fluphenazine decanoate Oily Gluteal, every two to five weeks 1968 Pipotiazine palmitate Oily Gluteal, every four weeks 1983 Risperidone Powder for reconstitution with Gluteal or deltoid, every two weeks; 2002 aqueous solution in a prefilled requires refrigeration syringe, forms a suspension Paliperidone palmitate Powder for reconstitution with Gluteal or deltoid, every four weeks; 2011 aqueous solution in a prefilled no refrigeration required syringe, forms a suspension Olanzapine embonate Powder for reconstitution with Gluteal, every two or four weeks; 2010 aqueous fluid, forms a observe patient carefully for symptoms suspension of post-injection syndrome for three hours after each dose Table 2. Depot antipsychotics currently available in the UK 12 Progress in Neurology and Psychiatry May/June

6 Antipsychotics for schizophrenia z Review Drug Levels increased by Levels decreased by Increases levels of Additional information* Typical antipsychotics (by BNF listing) Chlorpromazine Cimetidine, propranolol, Antacids containing Propranolol, Increased risk of ventricular some antimalarials (chloroquine, aluminium/magnesium carbamazepine, arrhythmias when given with Fansidar [ie sulfadoxine/ hydroxide or magnesium phenytoin (or may anti-arrhythmics pyrimethamine]) trisilicate, phenobarbital be lowered) Flupentixol Fluphenazine Carbamazepine Increased risk of ventricular arrhythmias when given with anti-arrhythmics Haloperidol Buspirone, fluoxetine, Rifampicin, carbamazepine, Carbamazepine Increased risk of ventricular fluvoxamine, indometacin, celecoxib, phenobarbital, arrhythmias when given with itraconazole, quinine, phenytoin anti-arrhythmics ritonavir, venlafaxine Avoid concomitant use with saquinavir as may prolong QTc Pimozide Atazanavir, efavirenz, indinavir, Increased risk of ventricular paroxetine, fluvoxamine, arrhythmias when given with any fluoxetine, sertraline, agent affecting cardiac rhythm saquinavir, azole antimycotics, (NB. CSM warning). Refer to BNF macrolide antibiotics, for further details. Avoid cilostazol, clarithromycin, concomitant use of saquinavir as grapefruit juice may prolong QTc. Increased risk of hypokalaemia when given with diuretics Pipotiazine Cimetidine, ritonavir Increased risk of ventricular palmitate arrhythmias when given with anti-arrhythmics. Avoid concomitant use of saquinavir as may prolong QTc. Sulpiride Sucralfate, aluminium / magnesium hydroxide, antacids Trifluoperazine Zuclopenthixol Increased risk of ventricular arrhythmias when given with anti-arrhythmics Increased risk of ventricular arrhythmias when given with anti-arrhythmics Atypical antipsychotics (by BNF listing) Amisulpride Aripiprazole Fosamprenavir, atazanavir, Carbamazepine, efavirenz, diltiazem, escitalopram, nevirapine, phenytoin, fluoxetine, indinavir, phenobarbital, primidone itraconazole, ketoconazole, St John s wort, rifampicin, lopinavir, ritonavir, saquinavir, rifabutin paroxetine Table 3. Examples of clinically significant drug-drug interactions associated with commonly used antipsychotics 8,31 *See notes in Box 2 Progress in Neurology and Psychiatry May/June

7 Drug Levels increased by Levels decreased by Increases levels of Additional information* Atypical antipsychotics (by BNF listing) Clozapine Caffeine, cimetidine, Carbamazepine, phenytoin, Highly protein bound Avoid concomitant use with drugs erythromycin and risk of celecoxib, phenobarbital, drugs (eg warfarin and that have a substantial potential convulsions, ciprofloxacin, rifampicin, valproate digoxin) due to for causing agranulocytosis, ritonavir, fluoxetine, fluvoxamine, smoking (tobacco) displacement from including all depot antipsychotics paroxetine, sertraline, venlafaxine, plasma proteins and cytotoxics. valproate Possibly enhances CNS toxicity of MAOIs Avoid concomitant use with saquinivir as may prolong QTc Olanzapine Ciprofloxacin, fluvoxamine Carbamazepine, ritonavir, Increased risk of neutropenia when valproate, smoking (tobacco) given with valproate. Increased risk of hypotension, bradycardia and respiratory depression when IM is given with parenteral benzodiazepines Paliperidone Carbamazepine, rifampicin The bioavailability of paliperidone may be increased if taken with a high fat/high calorie meal or decreased if taken with metoclopramide Quetiapine Erythromycin, ketoconazole and Carbamazepine, barbiturates Carbamazepine other azole antimycotics, phenytoin, rifampicin grapefruit juice Risperidone Bupropion, duloxetine, Carbamazepine, celecoxib, Carbamazepine Neuroleptic malignant syndrome fluoxetine, itraconazole fluoxetine, paroxetine, has developed in patients taking phenytoin, rifampicin risperidone with indinavir and ritonavir Table 3. Examples of clinically significant drug-drug interactions associated with commonly used antipsychotics (cont.) 8,31 *See notes in Box 2 Metabolic syndrome Metabolic syndrome has become a major concern over recent years. It has been described as a cluster of abnormalities that increase the risk of cardiovascular disease, namely: obesity hyperlipidaemia hypertension hyperglycaemia. This syndrome can arise in a number of situations. Schizophrenia per se can increase the risk of cardiovascular disease, but metabolic syndrome has also been linked with the use of antipsychotics and greater emphasis has been put on prescribers to proactively review patients for changes in these parameters. 32,33 Antipsychotics can cause weight gain, which seems to result from increased food intake and in some cases reduced energy expenditure. 5,10 Most weight is gained during the first three to four months of treatment, although can continue for much longer 34 (see Table 1). Patients should be advised preferably at the beginning of treatment of the risks of weight gain with specific antipsychotics and how to prevent this; they should be encouraged to monitor their own weight and be advised about lifestyle changes such as a healthy diet and physical exercise. Secondly, some antipsychotics can also disturb the lipid balance potential leading to or aggravating the onset of hyperlipidaemia (eg high risk: clozapine, olanzapine; moderate risk: quetiapine; minimal risk: risperidone). Thirdly some antipsychotics can also disturb the glucose balance potential leading to or aggravating the onset of hyperglycaemia (eg high risk: clozapine, olanzapine; moderate risk: quetiapine; minimal risk: risperidone). Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening neurological disorder most often precipitated by the use of antipsychotics. It can be complex to diagnose as there are 14 Progress in Neurology and Psychiatry May/June

8 Antipsychotics for schizophrenia z Review commonly many confounding factors, and it can be confused with catatonia. 5,10 Symptoms include hyperthermia, profuse sweating, tachycardia, unstable blood pressure, confusion, fluctuating levels of consciousness, muscular rigidity, incontinence and a raised creatine phospho kinase (CPK) (see Figure 2). There is no recognised spectrum of severity of symptoms. As the name suggests it may be caused by any antipsychotic (previously known as neuroleptics ), both typical and atypical. It is hypothesised that it is due to an over-blockade of the dopaminergic system. NMS has also been reported with other agents that affect the dopaminergic system. 10 Symptoms usually last for five to seven days after discontinuing the suspected causal agent. Re-challenging with antipsychotics is inherently associated with a risk of precipitating a repeat episode of NMS, and therefore should be done very cautiously. It is recommended that antipsychotics are not re-started for about a week after NMS, and only after symptoms have completely resolved. For an overview of other adverse effects of anti - psychotics, refer to Monitoring unwanted effects of antipsychotics (Drugs and Therapeutics Bulletin 2011). 32 Adherence There are numerous studies and literature reviews published reporting and analysing patients rates of non-adherence or non-compliance with prescribed psychotropics, and an even wider literature covering other prescribed medicines, 5,36 including NICE guidelines. 37 Reported rates of non-adherence or partial adherence with psychotropics in the in patient and outpatient settings are commonly low but vary widely from 24 to 90 per cent Reviews of studied rates of non-adherence with psychotropics show that these do not differ greatly from those reported with a wide range of other medicines prescribed for medical conditions (60-92 per cent). 40,41 Non-adherence is a multifactorial and complex behaviour that has been widely studied in many settings. A number of reasons and factors in patients non-adherence with prescribed psychotropics have been cited in several studies. 37,41-45 Such high rates of partial or non-adherence with psychotropics is of great concern as it is a significant barrier in the delivery of effective pharmacological treatment for a range of mental illnesses, 41,43 and the impact of this partial or non-adherence may be underestimated. Missing doses, taking a lower dose, or even stopping the medicine completely does not usually lead to an immediate full-blown relapse of the psychiatric illness (although it may). In the short term it may lead to an exacerbation of symptoms, and in the medium *All antipsychotics potentially antagonise the anticonvulsant effect of antiepileptic agents *All antipsychotics enhance the response to alcohol, anxiolytics and hypnotics, opioid analgesics, the effects of barbiturates and other CNS depressants *Increased risk of toxicity when myelosuppressive drugs are given *Enhanced hypotensive effects when general anaesthetics are given *Lithium may increase CNS toxicity with any antipsychotic *All antipsychotics antagonise the effect of levodopa and other direct and indirect dopamine agonists Box 2. Additional notes to supplement Table 3 and longer term it is associated with an increased rate of psychiatric relapse, 46 increased hospital admissions, 47 and may lead to a poorer prognosis and selfinjurious behaviour. 41 In one study, the mortality rates among non-compliant people with schizophrenia were 10-fold higher than in those taking antipsychotics, and the risk of suicide was also increased. 48 Therefore it is extremely important for healthcare professionals to try to engage in a collaborative approach to prescribing with each individual, in order to optimise their likelihood to regularly take the medicines prescribed in the agreed treatment plan. Future developments Future research is likely to focus on agents with minimal side-effects (both those common to the typicals and atypicals), with improved efficacy on negative symptoms and cognitive function. This is alongside substantial ongoing work in the field of pharmaco - genetics, ie the study of the genetic variations in people with schizophrenia that give rise to differing responses to antipsychotics. There are a number of antipsychotics currently under development (sum- Diarrhoea Mild symptoms Profuse sweating High fever Muscular rigidity Incontinence Confusion and altered consciousness Unstable BP and pulse Figure 2. The spectrum of symptoms of neuroleptic malignant syndrome Convulsions Ataxia Life threatening Progress in Neurology and Psychiatry May/June

9 High propensity to cause weight gain ie a third or more of patients may gain >7% of baseline weight Clozapine Olanzapine Moderate risk ie 10-20% of patients may gain >7% of baseline weight Quetiapine Chlorpromazine Risperidone Low risk ie <10% of patients may gain >7% of baseline weight Amisulpride Aripiprazole Haloperidol Significant weight gain has been defined as an increase >7% from baseline Box 3. Risk of weight gain associated with antipsychotics 10,13,35 marised in Table 4), and several existing medicines are being investigated for their potential antipsychotic properties, eg minocycline, 49 oestrogen. 50 Summary It is critical to optimise the mental health of those who suffer from illnesses such as schizophrenia, as poor mental health impacts on individuals physical health and wellbeing, is a major cause of incapacity and poor social functioning, and places a significant burden on society. Mental health has therefore been nationally identified as an area for improvement. 55 The majority of those suffering with severe enduring mental illnesses are commonly asked to take medication for long periods of time, and often indefinitely. Patients with schizophrenia would have an improved experience in relation to medicines if they: were given the opportunity to openly discuss their medication regimens with healthcare professionals were given appropriate information about their Drug Comment Current stage Manufacturer Expected UK in development launch date Aripiprazole depot 52 Lyophilised (freeze-dried) powder EMA application filed for Lundbeck Trials ongoing for reconstitution into a maintenance in schizophrenia into 2014 suspension. Once-monthly IM injection Bitopertin (oral) Glycine transporter-1 (GlyT1) Phase 3 clinical trials Roche 2015 inhibitor, first in its class. For persistent, predominant negative symptoms of schizophrenia Blonanserin 53 Launched in Japan and Korea in Dainippon? 2010 Sumitoma Iloperidone (oral) 54 Approved in the USA. EMA EMA application filed Novartis - refusal of marketing authorisation December 2012 Iloperidone depot Water based depot administered Novartis/Vanda? every four weeks Pharmaceuticals Loxapine Typical antipsychotic. Approved EMA application filed and Alexza November 2013 (inhalation) in USA for the treatment of recommended for approval. Pharmaceuticals agitation in schizophrenia/bipolar NICE Technology Appraisal disorder terminated (May 2013) Lurasidone Launched in the USA EMA has accepted marketing Sunovion Quarter 4, 2013 (oral) February 2011 approval application Paliperidone Three-monthly IM injection Phase 3 clinical trials Janssen-Cilag Trials ongoing palmitate until 2014 Table 4. Antipsychotics in late stage development 34,51 16 Progress in Neurology and Psychiatry May/June

10 Antipsychotics for schizophrenia z Review Antipsychotics are an effective treatment for the majority of those with schizophrenia As with all medication antipsychotics can cause adverse reactions. Many adverse reactions such as dizziness and drowsiness wear off within the first few days of taking the medicine. Other adverse reactions such as weight gain and changes in women s menstrual periods may develop later, and these should be discussed with your psychiatrist or pharmacist Antipsychotics are not addictive Antipsychotics are usually taken for a long period of time, eg at least six months. Exactly how long will depend on the nature of your illness; you should discuss this with your psychiatrist Even when you are feeling better, it is important to carry on taking your antipsychotic, as it is there to protect your mental health, and to prevent you from becoming ill. Do not stop it on your own discuss this with your psychiatrist It is important to inform your psychiatrist/ pharmacist of any other prescribed, purchased or herbal medication when discussing your medicines Box 4. Key information for patients about antipsychotics medicines and how thet should be taken (see Box 4) develop a good understanding of the potential benefits of their medication understand the adverse effects to watch out for knew how to access help in the event of a medication-related problem. Giving patients support in these areas is known to increase compliance with prescribed medication, 42 whereas non-compliance is associated with relapse and poorer patient outcomes. 44 Declaration of interests None declared. Caroline Parker is a Consultant Pharmacist, Adult Mental Health Services, at Central and North West London NHS Foundation Trust References 1. Singleton N, Bumpstead R, O Brien M, et al. Psychiatric Morbidity Among Adults Living in Private Households, Report of a survey carried out by the Social Survey Division of the Office for National Statistics on behalf of the Department of Health, the Scottish Executive and the National Assembly for Wales. London: HMSO. 2. World Health Organization. ICD-10 Classification of Mental and Behavioural Disorders. Clinical description and diagnostic guidelines. 10th revision. Geneva: WHO, Marshall M, Lewis S, Lockwood A, et al. Association between duration of untreated psychosis and outcome in cohorts of first-episode patients: a systematic review. Arch Gen Psychiatry 2005;62: National Institute for Health and Clinical Excellence. Clinical Guideline 1. Schizophrenia: Core interventions in the treatment and management of schizophrenia in primary and secondary care. NICE, Barnes RE, and the Schizophrenia Consensus Group of the British Association for Psychopharmacology. Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2011;25(5): Kane J, Honefield G, Singer J, et al. Clozapine for the treatment resistant schizophrenic. Arch Gen Psychiatry 1988:45; Reilly JG, Ayis SA, Ferrier IN, et al. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Lancet 2000; 355(9209); British National Formulary, 65th edn. London: BMJ Publishing Group Ltd and the Royal Pharmaceutical Society of Great Britain, February British National Formulary for Children, edn. London: BMJ Publishing Group Ltd, the Royal Pharmaceutical Society of Great Britain and RCPCH Publications Ltd, Taylor D, Carol P, Kapur S. The Maudsley Prescribing Guidelines in Psychiatry, 11th edn. London: Wiley-Blackwell, Bhattacharjee J, El-Sayeh HGG. Aripiprazole versus typicals for schizo phrenia. Cochrane Database of Systematic Reviews 2008, issue 3. Art no: CD DOI: / CD pub3 12. Jones PB, Barnes TR, Davies L, et al. Randomised controlled trial of the effect on quality of life of second- vs. first-generation antipsychotic drugs in schizophrenia. Cost utility of the latest antipsychotic drugs in schizophrenia study (CUtLASS-1). Arch Gen Psychiatry 2006; 63: Lieberman J, Stroup TS, McEvoy J, et al. (Clinical Antipsychotics Trials of Intervention Effectiveness [CATIE] Investigators). Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353(12): Stroup TS, Lieberman JA, McEvoy J, et al. Effectiveness of olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia after discontinuing perphenazine: a CATIE study. Am J Psychiatry 2007;164(3): Hartling L, Abou Setta AM, Dursun S, et al. Antipsychotics in adults with schizophrenia: Comparative effectiveness of first-generation versus second-generation medications. Ann Intern Med 2012;157(7): Ilyas S, Moncrieff J. Trends in prescriptions and costs of drugs for mental disorders in England, Br J Psychiatry 2012;200: Taylor DM, Young C, Paton C. Prior antipsychotic prescribing in patients currently receiving clozapine: A case note review. J Clin Psychiatry 2003;64: Nasrallah HA. The case for long-acting antipsychotic agents in a post-catie era. Acta Psychiatrica 2007;115: Barnes TRF, Shingleton-Smith A, Paton C. Antipsychotic long-acting injections: prescribing practice in the UK. Br J Psychiatry 2009;195:S37-S Adams CE, Fenton M, Quraishi S, et al. Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. Br J Psychiatry 2001;179: Shajahan P, Spence E, Taylor M, et al. Comparison of the effectiveness of depot antipsychotic in routine clinical practice. The Psychiatrist 2010;34: Second-generation long-acting injectable antispcyhotic agents: and overview. Drugs and Therapeutics Bulletin 2011;50(9): National Institute for Health and Clinical Excellence. Clinical Guideline 155. Psychosis and schizophrenia in children and young people: recognition and management. NICE, Meltzer HY, Burnett S, Bastani B, et al. Effects of six months clozapine treatment on the quality of life of chronic schizophrenic patients. Hosp Comm Psychiatry 1990;41: Meltzer HY. Clozapine: is another view valid? Am J Psychiatry 1995;152(6): Lewis SW, Barnes TR, Davies L, et al. Randomised controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull 2006; 32(4): McEvoy JP, Lieberman JA, Stroup TS, et al, for the CATIE Investigators. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry Progress in Neurology and Psychiatry May/June

11 2006;163: Meltzer HY. Suicide and schizophrenia: clozapine and the InterSePT study. J Clin Psychiatry 1999;60(suppl. 12): Clozapine (Clozaril) Summary of Product Characteristics. Novartis Pharmaceuticals UK Ltd. Last updated on the emc 16 August Electronic Medicines Compendium Asenapine (Sycrest) Summary of Product Characteristics. Lundbeck Ltd. Last updated on the emc 29 January Electronic Medicines Compendium Baxter K. Stockley s Drug Interactions. RPS Publishing, Monitoring unwanted effects of antipsychotics. Drugs and Therapeutics Bull 2011;49(10): Atypical (second-generation) antipsycotics: reminder to monitor and manage weight, glucose and lipids. Drug Safety Update 2011;4(9): H Bazire S. Psychotropic Drug Directory Warwickshire: Lloyd- Reinhold Communications LLP, Allison D, Mentore JL, Heo M, et al. Antipsychotic induced weight gain: A comprehensive research synthesis. Am J Psychiatry 1999;156: Haynes RB, McDonald H, Garg AX, et al. Interventions for helping patients to follow prescriptions for medications. Cochrane Database of System Reviews 2002;issue 2. Art no: CD National Institute for Health and Clinical Excellence. Clinical Guideline 76. Medicine adherence: Involving patients in decisions about prescribed medicines and supporting adherence. NICE, Nose M, Barbul C, Tansella M. How often do patients with psychosis fail to adhere to treatment programmes? A systematic review. Psychological Med 2003;33(7); Corrigan PW, Liberman RP, Engel JD. From non-compliance to collaboration in the treatment of schizophrenia. Hospital Community Psychiatry [online] 1990;41(11); Accessed 15 March Cramer JA, Rosenheck R. Compliance with medication regimens for mental and physical disorders. Psychiatric Services 1998;49; Keith SJ, Kane JM. Partial compliance and patient consequences in schizophrenia: Our patients can do better. J Clin Psychiatry 2003;64(11): Cooper C, Bebbington P, King M, et al. Why people do not take their psychotropic drugs as prescribed: results of the year 2000 National Psychiatric Morbidity Survey. Acta Psychiatr Scand 2007;116: Perkins DO, Gu H, Weiden PJ, et al. Predictors of treatment discontinuation and medication nonadherence in patients recovering from a first episode of schizophrenia, schizophreniform disorder, or schizo - affective disorder. J Clin Psychiatry 2008;69(1); Fenton WS, Blyler CR, Heinssen RK. Determinants of medication compliance in schizophrenia. Schizophr Bull 1997;23(4): Loffler W, Kilian R, Toumi M, et al. Schizophrenic patients subjective reasons for compliance and non-compliance with neuroleptic treatment. Pharmacopsychiatry [online] 2003;3(3): Abstract from PubMed. Accessed 15 March Robinson D, Woerner MG, Alvir JM, et al. Predictors of relapse following response from a first episode schizophrenia or schizoaffective disorder. Arch Gen Psychiatry 1999;56; Weiden P, Glazer W. Assessment and treatment selection for revolving door inpatients with schizophrenia. Psychiatr Quart 1997;68(4): Tiihonen J, Walhbeck K, Lönnqvist J, et al. Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ 2006;333: Dean OM, Data-Franco J, Giorlando F, et al. Minocycline: therapeutic potential in psychiatry. CNS Drugs 2012;26(5): Kulkarni J, Gavrilidis E, Worsley R, et al. Role fo estrogen treatment in the management of schizophrenia. CNS Drugs 2012;26(7): UKMi New Drugs Online. Database last updated 19 February Kane JM, Sanchez R, Perry PP, et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia. J Clin Psychiatry 2012;73(5): Deeks ED, Keating GM. Blonanserin: A review of its use in the management of schizophrenia. CNS Drugs 2010;24(1): Scott LJ. Iloperidone in schizophrenia. CNS Drugs 2009;23(10): Department of Health. Choosing Health: Making healthy choices easier. London: The Stationary Office, Progress in Neurology and Psychiatry May/June 2013