Risperidone

file

Dru

g pro

Risperidone

Background Each year about 1 in 10 000 persons get schizophrenia,l and the lifetime risk of the disorder is 0-9%. Patients may experience delusions, hallucinations, and thought disorder (positive symptoms) as well as avolition, social withdrawal, self-neglect, and blunted affect (negative symptoms). Schizophrenics are often unemployed and socially isolated, and this isolation may be responsible for antisocial behaviour and place a great burden on the family.3 The average cost to society per annum for the treatment of schizophrenia, in 1987 prices, is C 1670 ($2500).4 Chlorpromazine, the prototype antipsychotic drug, was introduced 40 years ago5 and revolutionised management. However, clinicians still face difficulties in the drug treatment of schizophrenia, including incomplete efficacy, especially in the negative syndrome, and unpleasant sideeffects such as undue sedation, autonomic symptoms, weight gain, and movement disorders. Among the movement disorders are drug-induced parkinsonism, akathisia, dystonias, and in chronically treated patients, tardive dyskinesia in about 25 % .6 More recently, attention has turned to the "atypical" neuroleptics, so called because they induce fewer movement disorders. However, all the existing atypical preparations have to be given orally and therefore depend on good compliance for success. Many patients do not take their drugs because they lack insight or volition, whereas others discontinue them because of intolerable side-effects. The introduction of long-acting intramuscular antipsychotic preparations in the 1960s has aided compliance, but patients must either consent or fulfil mental health legislation criteria for compulsory treatment. There is no single explanation to account for the reduced movement disorder with atypical drugs.7 All effective antipsychotic agents show some affinity for the dopamine2 (D2) receptor site that is thought to be responsible not only for the antipsychotic activity but also for movement abnormalities.8 The potential for D2 antagonism to cause movement disorder may be modulated by the addition of serotonin (S2) blockade in the spectrum of activity of drugs such as clozapine and thioridazine, and similarly with muscarinic blockade, again found with clozapine and thioridazine. However, there are other antisychotic drugseg, remoxipride and sulpiride-for which there is no ready explanation for the relative lack of movement disorder. Although the research and development programme for clozapine was abandoned in the 1960s when 8 patients died in early Finnish studies, observation of those who remained on the drug in some European centres, notably Germany and Denmark, suggested that it might be useful in treatment-resistant illnesses. A key study9 was carried out in the USA in 1988 by Kane and colleagues, who showed University Department of Psychological Medicine, Gartnavel Royal Hospital, 1055 Great Western Road, Glasgow, G12 0XH, UK (M G Livingston MD) Correspondence to: Dr M G Livingston

that clozapine improved the clinical outcome of about 30% of schizophrenics who had not responded to three types of antipsychotic drug followed by high-dose haloperidol. These results were confirmed, but added efficacy is often bought at the expense of side-effects. Although clozapine seldom causes movement disorder, 5% of patients on doses above 600 mg per day get epileptic seizures, others have embarrassing hypersalivation, and the high risk of agranulocytosis means that haematological monitoring is essential. Risperidone must therefore be compared with existing preparations with respect to (a) treatment of previously unresponsive patients and (b) better tolerability.

Mechanism of action

Risperidone is a benzisoxazole derivitive that combines S2 antagonism with D2 antagonism.10,11I Development of the molecule followed the observation that S2 antagonists such as ritanserin, when added to the regimen of patients on haloperidol, improved the treatment of negative symptoms, ameliorated depression and anxiety in schizophrenics, and reduced movement disorder.12 The improvement in movement disorder was confirmed when ritanserin was added to the treatment of patients on chlorpromazine, haloperidol, and fluphenazine. 13 potent

Low-afflnity dopamine, antagonist -

Improves positive symptoms of schizophrenia Limited induction of movement disorder

High-affinity serotonin2 antagonist Improves negative schizophrenic symptoms

-

Reduces movement disorder Improves mood change within schizophrenia

Table 1: Risperidone : combined serotonin and dopamine

antagonism

Although other neuroleptics combine S2 antagonism with D2 antagonism, the special properties of risperidone may be linked to its far greater affinity for S2 receptors than for D2 receptors (table 1)." Risperidone also has (xl and (1.2 noradrenergic activity and is antihistaminic. Although these actions are associated with side-effects, they are not thought to be relevant to the antipsychotic spectrum of activity. Clinical pharmacokinetics and its metabolite 9-hydroxyrisperidone constitute the antipsychotic fraction (figure) and have similar pharmacological profiles. The pharmacokinetics of both compounds are shown in table 2. Risperidone is rapidly absorbed and plasma concentration peaks about 2 h after injection; pharmacokinetics for doses between 0-5 and 25 mg per day are linear.14,15 Although single-dose studies have shown that risperidone is cleared normally in patients with liver insufficiency, with unaltered elimination halflife,16 a more pronounced pharmacological effect may be

Risperidone

457

Metabolism

Rapidly absorbed after oral administration Plasma peak reached in 2 h Hydroxylation and N-dealkylation

Elimination half-life

Slow metabolisers have low and fast metabolisers high concentrations of 9-hydroxyrispendone In extensive metabolisers, 2 4 h for risperidone and 27 h for

Steady state Bioavailability

9-hydroxyrisperidone Reached within 5-6 days 66% for the unchanged drug in fast metabolisers vs 82% in slow

Absorption

Distribution

Excretion

metabolisers Consistent with some first-pass metabolism Compensated for by generation of active metabolite Rapidly distributed Volume of distribution 1-2 L/kg Plasma binding to albumin and alpha,-acid glycoproteins Risperidone 88% bound to plasma protein vs 9-hydroxyrisperidone 77% 1 week after single dose: 70% excreted in urine, 14% in faeces

Table 2: Pharmacokinetic

Another

Figure: Molecular structure and metabolism of risperidone A = hydroxylation; B = N-dealkylation.

evident due

to

in

longer insufficiency.

are

increased unbound risperidone. Half-lives elderly patients and in those with renal

Efficacy Table 3 shows the main double-blind studies with risperidone. 17-24 In most cases patients were selected according to the US diagnostic system (DSM-III-R),25 by which operational criteria are used to define diagnoses and thus increase diagnostic reliability. The studies all show antipsychotic efficacy with significant improvements in total scores on the assessment instrument chosen; the results are similar to those of the comparison drug and/or significantly better than placebo. Efficacy in the treatment of negative symptoms is less clearcut. The US/Canada study19 of 523 subjects showed that risperidone in a strength of 6 mg per day was more effective than haloperidol 20 mg per day (p < 0-01) and placebo (p < 0-001) in the treatment of negative symptoms. However, a similar protocol employed in the multinational study20 of 1362 subjects did not show such superiority for risperidone in the treatment of negative symptoms. Whereas the US/Canada study used a fixed dose of 20 mg of haloperidol per day the multinational study dose was 10 mg. This discrepancy may account for the difference since risperidone could have been shown in an especially favourable light in the US/Canada study because the higher dose of haloperidol is more likely to produce parkinsonian symptoms which are easily rated as blunted affect, emotional withdrawal, and lack of spontaneity on the positive and negative symptom scale (PANSS).26 Furthermore, negative symptoms are difficult to measure and there is a lack of precision in their quantification. Cultural factors can also complicate the assessment of negative symptoms and contribute to the different results obtained from the two international studies 19,20 despite the use of a broadly similar protocol. 458

properties of risperidone

of keen interest

clinicians is

efficacy in previously non-responsive or poorly responsive patients. A Belgian study2l showed improvement in both positive and negative symptoms in a group of patients who received either risperidone or haloperidol after "optimisation" on their previous drug treatment. Although the main comparison drug has been haloperidol, reflecting its extensive worldwide use, antipsychotic efficacy for risperidone has been shown by comparison with methotrimeprazine,22 perphenazine,23 and clozapine.24 However, the clozapine study did not involve treatmentresistant patients. In Germany, clozapine is available for use in schizophrenia for indications other than treatment resistance. Risperidone also reduces anxiety and depression in patients with schizophrenia .20 Open-label studies27 suggest that risperidone is effective over a 12-month period area

to

and is well tolerated. When evaluting studies of antipsychotic drugs in schizophrenia we should remember that many of the patients have been on multiple drug therapies previously, that wash-out periods are seldom long enough to remove significant proportions of depot medication, and that the study populations are often highly skewed towards males because of the risks, in relation to pregnancy and lactation, of including women in the trials. Moreover, 4-8 weeks is often an insufficient time to permit an adequate treatment response in schizophrenia since the antipsychotic efficacy of a particular dose of drug may take 3-4 weeks to become manifest. The suggestion from the two dose-ranging international studies 19,20 that 4-8 mg per day of risperidone is optimum, or that there is a therapeutic window for the drug, must be regarded as tentative. Clinicians will be most interested to know whether risperidone is effective in the difficult-to-treat negative syndrome of schizophrenia, and here only the combined analysis of the US/Canada dataset19 has unequivocally shown risperidone to be better than another antipsychotic agent. There is insufficient evidence to indicate that risperidone is effective in treatmentresistant or poorly responsive cases, although data from a small double-blind study2l look promising. Further studies are required of dose-by-dose comparisons of risperidone with other antipsychotic agents, especially those less likely to induce movement disorder such as sulpiride and thioridazine. An ongoing Edinburgh trial may provide the necessary information on efficacy in treatment-resistant patients. Since many patients with schizophrenia are on medication indefinitely, long-term controlled data are essential. An international double-blind continuation study of risperidone vs

haloperidol may be helpful.

*Subgroup analysed from a larger study. BPRS = brief psychiatric rating scale; SANS = scale for the assessment of negative symptoms; PANSS = positive and negative symptoms scale; SADS-C schizophrenia (change version). Table 3: Double-blind studies of risperidone

Adverse

experience

Although minor somatic side-effects were reported in the clinical trials, many of these also occur with placebo19 so may be associated with schizophrenia rather than its treatment. Sedation is less likely to occur than with haloperidol, as are extrapyramidal side-effects. Risperidone in the 4-8 mg range does not differ from placebo with respect to extrapyramidal effects. 19 Risperidone produces postural hypotension as might be expected from the al adrenergic activity, but the effect is slight. An important side-effect is weight gain, which is a neglected but common complication of antipsychotic agents. In the open-label long-term studies weight gain averaged 23 kg.27 The drug also causes a dose-related rise in prolactin, like other D2 blocking drugs, and consequently menstrual upset, galactorrhoea, gynaecomastia, and decreased libido. Growth hormone, thyrotropin, triiodothyronine, and cortisol are unchanged by the drug, as are routine haematological and biochemical tests.

Drug interactions information about interactions with risperidone although one might anticipate difficulties with concurrent administration of dopamine agonists (eg, for parkinsonism) or with drugs that produce postural hypotension, (eg, many tricyclic antidepressants, other antipsychotic agents, and alcohol). Excessive sedation may occur with concomitant admission of antihistamines. There

is

Clinical

little

= schedule for affective disorders and

Care will be necessary in elderly patients and those with cardiovascular disease because of the risk of postural hypotension, and in those with renal and liver impairment. Despite the beneficial profile in terms of movement disorder, one should not assume that risperidone is safe in those who have experienced the neuroleptic malignant syndrome. If the benefits of risperidone arise from a balance between D2 and S2 blockade, it would seem irrational to use the drug as add-on therapy to bring acute schizophrenic episodes under control while patients remain on their depot or other antipsychotic preparations. The balance of S and D2 antagonism induced by risperidone would be disturbed by the concurrent treatment of a conventional antipsychotic drug with potent D2-blocking properties. Treatment should be initiated gradually to avoid postural hypotension-1 mg twice daily on day one, 2 mg twice daily on day two, and 3 mg twice daily on day three. The 3 mg dose should be maintained for several weeks to await an antipsychotic response. Thereafter, the dose may be increased gradually if required, but there is likely to be little overall clinical advantage above 10 mg per day. Above this dose the movement disorder profile more closely resembles haloperidol.19,20 In elderly patients or those with renal or liver disease, begin with 0-5 mg twice daily and increase the dose cautiously. The drug should not be given to children, pregnant women (in whom the safest option, if drug treatment is essential, is to use chlorpromazine whose risks are well known), or during lactation.

use

Who should get

risperidone? The main indications are prominent negative symptoms or intolerable movement disorder. For the latter indication, there are several other drugs with a relatively benevolent movement disorder profile, including well-established agents such as thioridazine and sulpiride. Risperidone is expensive—120 ($180) per month for 6 mg per day, the suggested optimal dose-and so is unlikely to become a first-line treatment for some time. Although its role in treatment-resistant cases needs further evaluation, it may be worth trying before turning to the more toxic clozapine. The lack of a depot preparation limits use to compliant patients or those who can readily be supervised.

Therapeutic potential Risperidone may improve tardive dyskinesia,16,18,19 and this possibility requires thorough evaluation. Other potential applications include the treatment of psychotic manifestations within manic depressive illness, especially as monotherapy for psychotic depression. Patients with dementia may benefit if they are deluded or have hallucinations.

References 1

Cooper JE, Goodhead T, Craig T, et al. The incidence of schizophrenia in Nottingham. Br J Psychiatry 1987; 151: 619-26. 459

Shields J. Genetics of schizophrenia. In: Wing JK, ed. Schizophrenia: towards a new synthesis. London: Academic Press, 1978: 56 3 The Scottish Schizophrenia Research Group. The Scottish First Episode Schizophrenia Study (IV). Psychiatric and social impact on relatives. Br J Psychiatry 1987; 150: 340-44. 4 Davies LM, Drummond MF. The economic burden of schizophrenia.

pharmacokinetics of risperidone in man. Janssen Clinical Research Report R 64 766 JRD 0005, March 1992. Obtainable from Janssen Pharmaceutical Ltd, Grove, Wantage, Oxon OX12 ODQ, UK Borison RL, Rathiraja AP, Bruce I, et al. Risperidone: clinical safety and efficacy in schizophrenia. Psychopharmacol Bull 1992; 28: 213-18. Chouinard G, Jones B, Remington G, et al. A Canadian multi-centre placebo controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 1993; 13: 25-40. Janssen Study Group. Risperidone versus haloperidol versus placebo in the treatment of chronic schizophrenia. Janssen Clinical Research Report RIS-INT-3, November 1991 (see ref 16). Janssen Study Group. Risperidone in the treatment of chronic schizophrenic patients: An international multi-centre, double-blind parallel group comparative study versus haloperidol. Janssen Clinical Research Report RIS-INT-2, January 1992. Claus A, Bollen J De Cuyper H, et al. Risperidone versus haloperidol in the treatment of chronic schizophrenic in-patients: a multi-centre, double-blind comparative study. Acta Psychiatr Scand 1992; 85:

2

Psychiatr Bull 1990; 14: 522-25. 5 Delay J, Deniker P, Harl JM. Traitement des états d’excitation et d’agitation par une methode medicamenteuse derivée de l’hibernotherapie. Ann Med Psychol 1952; 10 (pt 2): 267-73. 6 Yassa R, Jeste DV. Gender differences in tardive dyskinesia: a critical review of the literature. Schizo Bull 1992; 18: 701-15. Seeman P. Atypical neuroleptics: role of multiple receptors, endogenous dopamine, and receptor linkage. Acta Psychiatr Scand 1990; 82 (suppl 358): 14-20. Seeman P. Dopamine receptors and the dopamine hypothesis of

7

8

schizophrenia. Synapse 1987; 1: 133-52. Kane J, Honigfeld G, Singer J, et al. Clozapine for the treatment resistant schizophrenia: a double blind comparison versus chlorpromazine/benztropine. Arch Gen Psychiatry 1988; 45: 789-96. 10 Janssen PAJ, Niemegeers CJE, Awouters F, et al. Pharmacology of risperidone (R 64 7 6 6), a new anti-psychotic with serotonin-S2 and dopamine D2 antagonistic properties. J Pharmacol Exp Ther 1988; 244: 685-93. 11 Leysen JE, Gommeren W, Eens A, at al. Biochemical profile of risperidone: a new antipsychotic. J Pharmacol Exp Ther 1988; 247: 661-72. 12 Gelders Y, Vanden Bussche G, Reyntjens A, et al. Serotonin-S2 receptor blockers in the treatment of chronic schizophrenia. Clin Neuropharmacol 1986; 9 (suppl 4): 325-27. 13 Bersani G, Grispini A, Marini S, et al. Neuroleptic induced extrapyramidal side-effects: clinical perspectives with ritanserin (R55667), a new selective 5-HT2 receptor blocking agent. Curr Ther Res 1986; 40: 492-99. 14 Roose K, Gelders YG, Heylen S. Risperidone (R64 766) in psychotic patients: a first clinical therapeutic exploration. Acta Psychiatr Belg 1988; 88: 233-41. 15 Mesotten F, Suy E, Pietquin M, et al. Therapeutic effect and safety of increasing doses of risperidone (R64 766) in psychotic patients. Psychopharmacol 1989; 99: 445-49. 16 Sach MR. The effects of age, renal and liver impairment on the

17 18

19

20

21

9

295-305. 22 Tatossian A, Blin O.

Comparative double-blind study of the efficacy of risperidone, haloperidol, and levomepromazine in patients with an acute exacerbation of schizophrenia presenting psychotic anxiety symptoms. Janssen Clinical Research Report RIS-FRA-9003,

November, 1991 (see ref 16). Hoyberg OJ, Fensbo J, et al. Risperidone verus perphenazine in the treatment of chronic schizophrenic patients with acute exacerbations. Acta Psychiatr Scand (in press). 24 Klieser E, Kinzler E. Risperidone versus clozapine in the treatment of schizophrenic patients with acute symptoms: a double-blind randomised trial. Janssen Clinical Research Report RIS-FRG-9005, August, 1991 (see ref 16). 25 American Psychiatric Association. Diagnostic and statistical manual of mental disorders, third edition, revised. Washington, DC: American Psychiatric Association, 1987. 26 Kaye SR, Fiszbein A, Opra LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schiz Bull 1980; 13: 261-76. 27 Mertens C. Risperidone treatment in psychotic patients: a combined analysis. Three open long-term trials. Janssen Clinical Research Report RIS-INT-8, RIS-BEL-17, RIS-HOL-9002, February, 1992 (see ref 16).

23

Viewpoint The Gods of the Comic-book Headlines*

In the

As I pass through my reincarnations in every age and course, I make my proper prostrations to the gods of the market force.

And the Gods of the Comic-book Headlines, I notice, outlast them all.

market-led economy we were promised abundance for all, By robbing collective Peter to pay for selective Paul; But, though we had plenty of money, there was nothing our money could buy, And the Gods of the Comic-book Headlines said "If you don’t work you die".

When Thatcher’s

With the

Peering through reverent fingers I watch them flourish and fall,

Contract was perpetual peace.

new

forming,

They promised They swore, if we gave up our birthright that the wars of the parties would cease. But when we demurred they stuffed us and delivered us bound to our foe, And the Gods of the Comic-book Headlines said "Stick to the Devil you know". 460

new

hopes that our world is built on they were utterly out of touch They denied that the moon was stilton; they denied she was even Dutch. They denied that managers were robots; they denied that mandarins had wings So we worshipped the Gods of the Market who promised us beautiful things.