Editorials

Treatment resistance in schizophrenia

Since the 1950s, when chlorpromazine was introduced into psychiatric practice, antipsychotic drugs have been the cornerstone of the management of schizophrenia. They have three main functions: to treat the positive symptoms of acute schizophrenic episodes; to reduce schizophrenic relapse; and to manage the negative features of schizophrenia, although the evidence for their efficacy in this area is weaker. It is in relation to positive symptoms that the term treatment resistance is generally used. While the concept of treatment resistance remains ill defined, recent advances in drug treatment may bring better understanding of its underlying mechanisms.

It has been evident for many years that some cases of schizophrenia are resistant to treatment. In trials of conventional antipsychotic drugs about 30% of acute cases show only limited improvement¹ and about 7% of these patients seem to show no response from the start of their illness.² But the concept of treatment resistance remains ill defined. Kane et al used an operational definition--patients who failed to respond to two conventional antipsychotic drugs for six weeks³--while others have suggested a grading system ranging from total remission within one week on any treatment, to failure to respond after six months of drug and social treatment in hospital.⁴ Complete recovery with a sustained return to best premorbid functioning is not usual in patients with schizophrenia, and the point at which patients who do not materially improve can be described as resistant to treatment is therefore arbitrary. It is important to realise that not all patients who fail to respond are resistant to treatment; some may have received suboptimal treatment, perhaps because of poor compliance. However, limited response to treatment certainly occurs when drugs are being taken correctly, adequate plasma concentrations are achieved, and there is laboratory evidence of dopamine receptor blockade.⁵

More than just D2 dopamine receptor blockade

The reality of treatment resistance in schizophrenia is emphasised by recent studies conducted on violent schizophrenic patients in special hospitals in England and Scotland.^{6 7} These patients are energetically treated with traditional and newer antipsychotic drugs in circumstances where compliance is as assured as it can ever be, and yet positive symptoms not only persist but are the basis in many cases of continuing disturbed and distressing behaviour. These patients are, of course, at the extreme end of the continuum of severity of schizophrenic illness, but our knowledge of why some should prove so resistant to therapeutic effort is sadly lacking.

In 1988 Kane et al caused an upsurge in interest in treatment resistance with their demonstration that schizophrenic patients who fulfilled an operational definition for treatment resistance showed definite group benefits when treated with clozapine as compared with standard treatment.³ Clozapine had been shown to be an effective antipsychotic drug in the 1970s, but its association with agranulocytosis (cumulative incidence of 0.8% after one year of exposure)⁸ delayed its widespread use. Its enhanced efficacy has been confirmed in subsequent trials and has changed our understanding of the mechanisms underlying antipsychotic treatment. Previous attempts to develop new antipsychotic drugs had been influenced by the dopamine hypothesis, supported by the observation that all effective antipsychotic drugs exhibited some degree of D2 dopamine receptor antagonism.⁹ The fact that clozapine is only a weak D2 blocker suggests that mechanisms other than D2 blockade must be relevant for the control of positive symptoms. We do not know which of the neurotransmitter mechanisms affected by clozapine (dopamine receptor subtypes, serotonin, or (alpha) adrenergic effects) is responsible for its benefits in patients who are resistant to treatment. Another drug with evidence of enhanced effectiveness, risperidone, has D2 and 5HT2 receptor blocking properties.¹⁰ Clarifying the mode of action of more effective drugs is likely to provide a key to understanding treatment resistance.

Imaging links symptoms and brain function

Other approaches are also bearing fruit. Functional imaging techniques have considerable potential for examining the relations between psychotic symptoms, performance in neuropsychological tests, response to drug treatment, and blood flow in different regions of the brain. Positron emission tomography has shown that different symptom patterns in patients with schizophrenia produce different patterns of cerebral blood flow.¹¹ Functional magnetic resonance imaging, which does not involve ionising radiation and permits multiple repeat examinations, may clarify the relation between symptom patterns, drug effects, and regional brain function. Such work may allow the considerable theoretical advances that have occurred in schizophrenia research over the past 20 years to start to be translated into therapeutic benefit for current sufferers.

Professor of psychiatry Lecturer in psychiatry Department of Psychiatry, Royal Edinburgh Hospital, Edinburgh EH10 5HF

Eve C Johnstone, Robert Sandler 

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