Drug treatment of refractory schizophrenia remains a major challenge, but clozapine continues to be gold standard

Schizophrenia is a crippling condition that often (in about 20-30% of patients) shows an inadequate response to first-line antipsychotic drugs. Because it is associated with significant, often devastating reductions in quality of life, the management of refractory cases of schizophrenia represents a major challenge to psychiatry. As pharmacotherapy is the treatment of choice, stringent guidelines are needed to optimise clinical management of such cases.

A recent clinical perspective by Dold and Leucht in the Evidence-Based Mental Health journal tries to summarise state-of-the-art evidence to provide clinicians with the knowledge they need to care for these patients.

Methods

The authors searched Medline with the keywords “antipsychotic*” or “schizophreni*”, which resulted in 46 studies that were included, so this should be considered a clinical review of the evidence rather than a comprehensive and systematic review of published and unpublished studies.

There is slightly more evidence for a switch of antipsychotic drug than for a high dose treatment

Results

Several strategies that can be used to deal with medically refractory schizophrenia are discussed:

Dose increase: Overall, escalation beyond approved dose ranges is not supported as a general recommendation. While some patients might benefit, it can be assumed that there is no linear relationship between antipsychotic efficacy and drug dose. In any case, occurrence and severity of adverse effects might increase, requiring additional monitoring.

Drug switching: While changing drug in case of non-response is often done, the jury is still out on whether this adaption of monotherapy is more effective. This is basically because individual drug efficacy has been established in trials with non-refractory patients, which makes generalisations to more severely ill populations difficult. Also, it is unclear whether there is any difference in antipsychotic efficacy among newer drugs at all. Overall, however, switching might be preferable to dose increases. In any case, highest chances of improvement can be expected in case of change to a compound with different chemical mechanisms than the original drug.
Treatment with clozapine: Clozapine is the gold standard for treatment resistant schizophrenia and overall there is highly convincing evidence in its favour. However, clozapine is somewhat of a mixed blessing due to low tolerability and potentially fatal agranulocytosis in around 1% of patients. Therefore, its administration demands careful medical supervision and may only be considered after appropriate, but unsuccessful treatment with two other antipsychotics. Currently, there is no clear evidence which drug to use in case of clozapine contraindication, but olanzapine or risperidone could be useful.

Combination strategies: While very often used in clinical practice, there is little evidence in favour of using two antipsychotics from the same group. From a pharmacological perspective, it makes most sense to combine current antipsychotics with clozapine because of its unique properties. However, any improvements in psychotic symptoms pale in comparison with increased rates and occurrence of adverse effects. Overall, premature discontinuation is significantly more likely when combinations of antipsychotics are used, while evidence suggests combination is superior to monotherapy in terms of mortality and hospitalisation rates.
Augmentation with other drug classes: This strategy evaluates adding drugs used to treat other conditions, such as mood-stabilisers used for bipolar disorder or antidepressants. Augmentation drugs might be useful for the treatment of specific symptoms, including comorbid depressive disorder or agitation, but they fail to achieve significant improvement in the long-run.

There is currently no convincing evidence to recommend combination antipsychotic treatment generally. This review recommends that antipsychotic monotherapy should be sought primarily

Limitations

Overall, the findings remain relatively confusing because the literature teems with differences in methodology, dosages and design.
Specifically, one of the main problems has been that drug efficacy is established in “ordinary”, non-refractory patients. From this perspective, any generalisation to treatment-resistant patients is very difficult.
Pharmacokinetic differences among patients can introduce bias in the analysis, as can smoking habits. To what extent this influenced the results of earlier studies remains to be thoroughly explored.
Lack of a consistent definition of what constitutes treatment resistance complicates comparison across studies.

Summary

Patients who fail to show adequate response to antipsychotic treatment remain a major challenge for clinicians. The lack of consistent information on possible treatment algorithms is unfortunately not abetted by this review. However, Dold and Leucht highlight the superiority of clozapine over other approaches in these cases. While clozapine comes at significant costs for patients, it has remained the gold standard up to date. In addition, augmentation from other drug classes could be helpful to tackle specific symptoms, such as depression. Overall, evidence does not support increasing dosage in case of non-response and there is only limited evidence in favour of switching to another drug from the same class.

The evidence points to Clozapine as the gold standard ﬁrst-line intervention in treatment-resistant schizophrenia, but a number of side effects often hamper its use in clinical practice