A case of resistant schizophrenia responding at a higher than recommended dose of risperidone without significant side effects.

A patient, diagnosed with schizophrenia, non-responsive to two atypical antipsychotics and partially responsive to the third (risperidone) in therapeutic dose, ultimately showed complete response without any unacceptable side-effect in a dose (20 mg) that was untried previously. This case makes an important observation that high dose of risperidone can be tried in a patient with good results if his clinical condition permits.

Introduction

Risperidone, an atypical antipsychotic of benzisoxazole group, is an antagonist at 5HT2A and D2 receptors. Although it is as potent a D2 antagonist as haloperidol, it is less likely to cause extrapyramidal symptoms (EPS). This benefit is non existent at higher dosage. Few studies have suggested that 6mg may be an optimal dose of risperidone for both positive and negative symptoms of schizophrenia, as, above that dose, the potential for side effect increases without added beneficial effect.[1-4] No study had been conducted over 16mg of risperidone. Risperidone has also been suggested as an effective treatment for a subset of resistant schizophrenia.[5] Here we present a case of a patient with schizophrenia, not adequately controlled by three antipsychotics, but responding to high dose of risperidone without developing significant side effects.

Case Report

A 28 year old man presented with active paranoid delusion and auditory hallucination since the last six years. He also gave a history of poly-substance abuse for more than ten years with two previous hospitalizations for aggravation of symptoms, but they were not adequately controlled even after treatment. His psychiatric symptoms could not be directly attributed to the substance abuse as the temporal relationship could not be established. On routine investigations and physical examination, all the parameters were normal (FBS- 106mg/ dl, PPBS- 128mg/dl, urea- 28mg/dl, cr-0.9mg/dl) except that the patient was overweight. He was diagnosed with schizophrenia as per Diagnostic and Statistical Manual - Text Revision (DSM- IV-TR) and was prescribed olanzapine 15 mg and sodium valproate 1000 mg for one month which resulted in only modest improvement of symptoms. The dose was escalated to 20mg without significant improvement. Considering the patient's weight, the regime was augmented with aripiprazole 5mg for two weeks and then switched to 10mg for four weeks with no improvement, and no clinical side effect was noted except a slight weight gain. A third antipsychotic, risperidone 3mg with trihexyphenidyl 2mg was added to the regime and improvement was seen within three weeks. Dose titration of risperidone upto 8mg (with trihexyphenidyl 4mg) was done and olanzapine was tapered off (considering the patient's weight). Complete symptom remission could not be achieved despite continuing risperidone 8mg, aripiprazole 10mg and sodium valproate 1000mg for the next six weeks. As the recommended dose of risperidone was already reached, dose of aripiprazole was raised to 15mg resulting in aggravation of symptoms. Olanzapine 15mg was restarted along with risperidone 12mg (along with trihexyphenidyl 6mg) in divided doses, and continued for more than three months. Improvement in patient's symptoms was seen with no tremors, EPS or other clinically notable side effects except weight gain. However, persistence of auditory hallucinations and delusional belief was noted though the frequency and intensity was reduced. Insight was not present.

To achieve complete symptom remission, the issue of raising the dose of risperidone was discussed with the patient's family members where lack of such case reports and available trials were weighed against advantage of higher dosage and lack of side effects in the specific patient and verbal consent was given for trial of higher dose of risperidone. Risperidone, 16mg (along with trihexyphenidyl 8mg) for four weeks showed further improvement but 20mg of risperidone (along with trihexyphenidyl 10mg) resulted in complete symptom remission after four weeks. Slowly all the concomitant medications (olanzapine and sodium valproate) were tapered off, but the symptom remission was maintained. The patient did not develop any tremors, other extrapyramidal symptoms or cognitive decline. However, a weight gain of 15 kgs was seen. The laboratory parameters were normal and elevation in prolactin levels was noted (59.3 mg/dl), which is expected in a case treated with risperidone at a normal recommended dose.

The patient has been on risperidone alone for the last two years with complete remission and no further episodes of symptom recurrence. The dose was slowly tapered to 10mg in search of an effective maintenance dose without reappearance of symptoms. His addictions are also under control.

Discussion

Although risperidone has established itself as a potent antipsychotic, no documented trials or case reports could be found where the dose of risperidone was more than 16mg. Clinicians do have reservations in trying higher dosage as previous evidence disfavours it.[12] In this particular case the medications used in higher dose gave favourable results without clinically significant adverse effects. This patient can be considered to be in the extreme range of population in terms of metabolism or pharmaco-genomics, in whom high dose of a medication can give good results without excessive adverse effects. While cases of adverse effects are many, positive results can also be a reason for the trial of higher dose of risperidone, provided it is clinically justified after proper precautions and adequate discussion. Higher dosage of risperidone can also be thought of as an option for treatment resistant schizophrenia. Further studies can be done focussing on this area.