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Is there a place for antipsychotic polypharmacotherapy in schizophrenia?

Since the introduction of the phenothiazines in the 1950s, physicians have used combinations of antipsychotic drugs to manage patients with schizophrenia, although this approach has provoked controversy. Antipsychotic drugs were traditionally considered to act by interfering with dopaminergic transmission in the CNS. All older 'typical' agents were assumed to have similar mechanisms of action, which implies that concurrent use of multiple agents is irrational. However, the introduction of the newer atypical antipsychotic agents, with their differing pharmacodynamic profiles, has rekindled interest in the use of combination therapy. Despite reservations over the amount and quality of data available to support the use of antipsychotic polypharmacotherapy, it has been possible to identify some groups of patients who might benefit from such treatment. [1]

Is combination therapy rational? It is possible that the use of combination therapy may

be attributable chiefly and quite simply to inappropriate prescribing, although it has also been suggested that clinicians are using drug combinations systematically to treat refractory symptoms in subgroups of patients. [1]

An estimated 5 to 25% of patients with schizophrenia have symptoms that are minimally responsive or unresponsive to traditional antipsychotic drug therapy)2] and as many as 60% of those who receive newer atypical agents (other than clozapine) show suboptimal responses according to psychiatric rating scale scoresJ3-6] Clozapine is generally considered to be the agent of choice for patients with treatment-resistant symptoms, but 40 to 70% of individuals so treated may show an inadequate response, and at least 30% are likely to withdraw from treatment because of adverse effects or excessively slow clinical improvement)?]

Substantial numbers of patients affected Despite the lack of consensus and scarcity of published

data on the use of more than 1 antipsychotic agent in individual patients with schizophrenia, this issue remains topical. In the light of the figures reported above, it is not surprising that antipsychotic polypharmacotherapy has been prescribed widely throughout the world. Surveys carried out over the last 30 years have shown the use of

t Mesoridazine is not available in Denmark, France, Germany and Spain.

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dual therapy in up to 40% of patients with schizophrenia, with a proportion of patients (up to 24%) receiving more than 2 agentsJI] Recent prescribing surveys show combination therapy being used in 4 to 25% of patients.[I]

Three basic treatment scenarios Conceptually, antipsychotic polypharmacotherapy

has been recommended for use during acute episodes of psychosis, for short term therapy during the transition from 1 therapy to another, and for the long term correction of inadequate response to monotherapy.[I]

Useful in acute psychosis . .. Prompt and effective treatment of acute psychosis is

important because patients with acute exacerbation of schizophrenia commonly display agitation and aggression, and may pose a threat to themselves or others. The simplest example of the application of combination antipsychotic pharmacotherapy in this setting is the addition on an 'as needed' basis of a typical antipsychotic agent to existing therapyJ!] A low potency injectable agent such as mesoridazine t may be particularly useful in these patients because there is less risk of extrapyramidal symptoms than with a more potent agent (e.g. haloperidol).

The illtrodllctioll of Hew atypical agellt 1111

rekindled illtere till cOIll/Jillfltioll tl,('/'tIp!!

Typical antipsychotic agents have also been given in combination with newer atypical drugs to control acute psychosis. The basis of this approach lies in the observation that atypical drugs are at least as effective as typical agents (particularly in the control of negative symptoms) but may act more slowly with respect to positive symptoms unless high dosages are usedJ8] There are no randomised controlled studies available to support such combinations, but anecdotal evidence[9] suggests that it may be helpful in these patients to start treatment with an atypical agent and a low dosage of a typical antipsychotic, and to taper off and eventually discontinue the typical agent as positive symptoms subside.

... and maybe when changing medication Abrupt discontinuation of psychotropic medication

can lead to withdrawal symptoms and exacerbation of psychiatric illness. This is because long term treatment with most psychotropic drugs results in adaptive changes

Vol. 16, No.3; July 31, 2000

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in the brain and subsequent physiological tolerance. The risk of withdrawal symptoms, dyskinesia and hospitalisation has prompted some clinicians to taper one psychotropic agent while titrating another.rll

Slow crossover from clozapine The case for slow overlap, taper and titration has been

reinforced by data from patients undergoing clozapine withdrawal. These results suggested that alterations in serotonergic function are responsible for withdrawal symptoms in patients being weaned off clozapine, and that a slow crossover to risperidone monotherapy [because of the affinity of risperidone for dopamine D2 receptors and its potent serotonin (5-hydroxytryptamine; 5-HT) 5-HT2A blocking effects] may be appropriate for patients who do not respond adequately to clozapineJIO,ll]

More information is needed A trend towards a lower rate of relapse was noted in

a small group of patients withdrawing from clozapine therapy who received concomitant perphenazine during the taper period (3 weeks) compared with those who did not. Symptomatic improvement was noted in 3 of 4 patients who received cyproheptadine (a serotonin receptor antagonist) in addition to clozapine and perphenazineJIO] However, another group of investigators found no link between crossover times and rates of relapse in a group of patients switching from clozapine to olanzapine treatment,P2] which underlines the need for more information on the use of dual antipsychotic agents in this setting.

Help for partial responders too Most patients with schizophrenia respond only partially

to antipsychotic mono therapy, and only modest succeSs

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45

40

35

30

25

20

15

10

5

0 Baseline 4 weeks after addition

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Fig. 1. Mean total 18-item Brief Psychiatric Rating Scale (BPRS) scores before and after addition of risperidone 2 to 6 mg/day for 4 weeks to clozapine therapy in 12 patients with treatment-resistant schizophrenia or schizoaffective disorderJ13] * p = 0.0002 vs mean baseline score.

Vol. 16, No.3; July 31,2000

has been achieved with combinations of typical agents. However, the introduction of the atypical antipsychotics, with their affinities for wide arrays of receptors, offers the potential for some patients to benefit from combined mechanisms of action. Limited evidence has indicated that combinations of 2 atypical drugs or a typical and an atypical agent might be useful in patients with treatment­resistant symptoms.[1] Combinations of atypical agents might also theoretically be used to mimic the activity of clozapine while avoiding the significant risk of agranulocytosis associated with use of this antipsychotic.

Scope to optimise clozapine therapy Inspection of dopamine and serotonin receptor binding

profiles suggest that combinations of clozapine and low dosages of risperidone might improve positive and negative symptoms of schizophrenia, without the adverse effects that might be seen with large dosages of clozapine, in some patients. The addition of risperidone 2 to 6 mg/day to clozapine therapy in 12 patients with treatment-resistant schizophrenia and schizoaffective disorder resulted in a reduction from baseline of over 20% in total I8-item Brief Psychiatric Rating Scale (BPRS) scores in 10 of these individuals (see figure 1).[13] In addition, 7 patients showed a reduction of at least 20% in negative symptom scores. Clozapine therapy has also been augmented in other small groups of patients with other drugs, including pimozide, loxapine, t olanzapine and haloperidol. [I]

Encouraging double-blind study results In the only double-blind placebo-controlled study

available, sulpiride (a selective dopamine D2 receptor antagonist) was added at dosages of up to 600 mg/day to clozapine therapy in 28 patients with schizophrenia and BPRSo-6 scores of at least 25 before randomisationJl4] Over 10 weeks, mean BPRSo-6 scores decreased by a mean 20.7%, with nearly 50% of patients achieving a mean reduction of 42.4%. There was no significant change in the clozapine/placebo group, and no significant difference in adverse effects between groups.

Problems with combination therapy

Minimal data available The main argument against the use of antipsychotic

polypharmacotherapy lies in the quality of data available to support this treatment approach; as discussed, only 1 controlled clinical study (which involved only a small number of patients) has been carried out. Other results have been obtained in an uncontrolled manner in small series of individuals.

t Loxapine is not available in Germany.

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Monotherapy trials with new treatments (atypical agents, including clozapine)

combination

'As-needed' adjunctive therapy with injectable typical agent

(e.g. mesoridazine)

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General recommendations for antipsychotic polypharmacotherapy in patients with schizophrenia[1 ]

Potential for adverse reactions and interactions

Patients with treatment-resistant symptoms of schizophrenia are likely to need high dosages of antipsychotic agents, with increased potential for adverse effects. Such individuals are also more likely to be elderly and to have other psychiatric or medical conditions, which may make them more susceptible to adverse reactions.[l]

Although clinical trial data are lacking, information on receptor binding and metabolic pathways of different antipsychotics can be used to attempt to predict adverse effects and drug-drug interactions. For example, older typical agents produce their beneficial effects via their affinity for dopaminergic receptors, but their various binding affinities for histaminergic, muscarinic and a-adrenergic receptors are responsible for a number of adverse effects. Thus, augmentation of clozapine (which also has affinity for these receptors) with typical antipsychotic therapy may result in more pronounced sedation, bodyweight gain, orthostatic hypotension and anticholinergic effects than might be seen with clozapine alone.[l]

Current knowledge of metabolic pathways does not indicate interactions to be likely with antipsychotic drug

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combinations, but additional research will be needed to clarify fully the potential for drug-drug interactions with atypical antipsychotics. [1]

Who should receive combination therapy? Although not enough is known about antipsychotic

polypharmacotherapy for the formulation of specific guidelines, it is possible to make some general recom­mendationsJl] These are summarised in the Patient care guidelines.

Combination therapy should be reserved for patients who do not respond adequately to mono therapy with atypical antipsychotic agents (including clozapine). In patients undergoing a change in medication, symptomatic improvement may be noted during the overlap period marking the transition from one atypical antipsychotic to another (during which 2 agents are being administered). If subsequent deterioration is noted after discontinuation of the original drug, the withdrawn agent may be reintroduced and the patient re-evaluated on combination therapy. Finally, as-needed doses of a second antipsychotic agent (rather than regular scheduled doses), with an increase in dosage of the original treatment if

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12

necessary, may be used to manage agitation or aggression in patients with acute exacerbation of schizophrenia.

Keep dosages low Antipsychotic agents with differing pharmacodynamic

profiles should ideally be selected to minimise (at least theoretically) any risk of adverse effects. The addition of low-dosage risperidone or sulpiride to clozapine therapy is an example of this approach. The risk of adverse effects may be reduced further through the selection of the lowest dosages possible, and patients should be treated for at least 4 to 6 weeks for proper evaluation of efficacy. BPRS and Positive and Negative Syndrome Scale (PANSS) scores are appropriate measures.

References I. Canales PL, Olsen J, Miller AL, et al. Role of antipsychotic

polypharmacotherapy in the treatment of schizophrenia. CNS Drugs 1999; 12: 179-88

2. Brenner HD, Denckner SJ, Goldstein MJ, et aI. Defining treatment refractoriness in schizophrenia. Schizophr Bull 1990; 16: 551-61

3. Satterlee W, Dellva MA, Beasley C, et al. Effectiveness of olanzapine in long-term continuation treatment. Presented at NCDEU: 1997 May; Boca Raton, Florida

4. Small JG, Hirsch SR, Arvanitis LA, et al. Quetiapine in patients with schizophrenia. A high- and low-dose double-blind comparison

with placebo. Seroquel Study Group. Arch Gen Psychiatry 1997; 54: 549-57

5. Zimbroff DL, Kane JM, Tamminga CA, and the Sertindole Study Group. Controlled, dose-response study of sertindole and haloperidol in the treatment of schizophrenia. Am J Psychiatry 1997; 154: 782-91

6. Harrigan EP, Reeves K. The efficacy and safety of low fixed doses of ziprasidone in schizophemia. Presented at NCDEU: 1997 May; Boca Raton, Florida

7. Kane J, Honigfeld G, Singer J, and the Clozaril Collaborative Study Group. Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1990; 47: 189-90

8. Beasley CM, Tollefson G, Tran P. Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology 1996; 14: 111-23

9. Anon. Clinical psychopharmacology online. Currents 1997; 16: 17-18

10. Meltzer HY, Lee MA, Ranjan R, et al. Relapse following ciozapine withdrawal: effect of neuroleptic drugs and cyproheptadine. Psychopharmacology 1996; 124: 176-87

II. Baldessarini RJ, Gardner OM, Garver DL. Conversions from ciozapine to other antipsychotic drugs. Arch Gen Psychiatry 1995; 52: 1071-2

12. Henderson DC, Nasrallah RA, Goff DC. Switching from ciozapine to olanzapine in treatment -refractory schizophrenia: safety, clinical efficacy, and predictors of response. J Clin Psychiatry 1998; 59: 585-8

13. Henderson DC, Goff DC. Risperidone as an adjunct to ciozapine therapy in chronic schizophrenics. J Clin Psychiatry 1996; 57: 395-7

14. Shiloh R, Zemishlany 0, Aizenberg 0, et al. Sulpiride augmentation in people with schizophrenia partially responsive to ciozapine. Br J Psychiatry 1997; 171: 569-73

OTe drugs can be harmful to the unborn child

Over-the-counter (OTC) drugs are readily accessible, widely used and, because they can be obtained without medical advice, are often perceived as being 'safe'.

Drugs in general should be avoided during pregnancy if possible. However, OTe drug usage during pregnancy is increasing because of advertising by the pharmaceutical industry and the lack of data showing the adverse effects of OTe preparations on the fetus.

OTe dYllg IIsage dllring pregnoncy i -illcrca ing

An increasing number of prescription drugs are being given OTe status. Some OTe drugs are known to adversely affect the fetus but drugs for which there is a lack of clinical data may also have the potential to produce adverse fetal effects when taken during pregnancy. In addition to the active drug, excipients of OTe preparations may affect fetal development. The effects on the fetus of an interaction between 2 OTe products or between an OTe product and a

Vol. 16, No.3; July 31, 2000

prescribed drug also need to be considered. In addition, some medications may present more risk to the fetus according to the stage of gestation (e.g. many medications are potentially harmful in the first trimester but pose less risk later in pregnancy). Pregnant women should be advised to consult a pharmacist or doctor before using any OTe medication.

OTe drugs are widely used ... Over recent years, an increasing number of drugs

have become available without the need for a prescription, primarily as the result of pressure from the pharmaceutical industry. [I] About 70% of adult illnesses are treated with OTe agents, but the enormity of OTe drug usage has recei ved little attention) I] Each year in the US billions of dollars are spent on a multitude of OTe products.[I]

.. . and are perceived as I safe' In general, the lay public believes that OTe drugs

are 'safe' and without any adverse fetal effects, primarily

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