A preliminary open trial of olanzapine in paediatric acute and transient psychotic disorders

Background: Acute and transient psychotic disorders (ATPD) have been characterized by the development of florid psychotic symptoms within 2 weeks and complete remission of symptoms. Although there are no definite guidelines, these are usually treated by antipsychotic medication. Aim: This preliminary study examined the ef fectiveness of olanzapine in paediatric A TPD. Methods: In this 6-week open trial of olanzapine in paediatric ATPD, the patients were rated weekly on the Brief Psychiatric Rating Scale (BPRS), Clinical Global Impression (CGI) Scale and Dosage Record Treatment Emergent Symptom Scale (DOTES). Results: Twenty-three patients (11 males, 12 females; mean age 14.0±1.3 years; range 1 1–16 years) were included in the study. The mean olanzapine dosage was 12.7±3.9 mg/day (range 5–20 mg/day). All the patients showed significant improvement in 6 weeks. The results showed a significant decrease (p<0.0001) in scores of BPRS (mean at baseline 46.2±7.0 to 21.4±3.9 at week 6). Severity of illness (CGI) decreased from 4.7±0.8 to 1.6±0.9 in 6 weeks. Also, global improvement (CGI) showed marked improvement in 14 (60.9%), good improvement in 8 (34.8%) and minimal improvement in 1 (4.3%) patient. Some common side-effects were dryness of mouth ( n =14, 60.9%), increase in appetite ( n =12, 52%), weight gain ( n =12, 52%) and drowsiness ( n =8, 34.8%). No patient developed extrapyramidal symptoms. Conclusion: Olanzapine was safe and effective in paediatric ATPD. Psychiatry

INTRODUCTION extrapyramidal symptoms (EPS), prolactin elevation and cognitive impairment. Atypical antipsychotics are used more Acute and transient psychotic disorders (A TPD) have been often in children because of these drugs have a better characterized by the development of florid psychotic tolerability profile. 6 symptoms within 2 weeks and complete remission of symptoms. 1 These may or may not be associated with stress.
There are few studies on the use of antipsychotic medication in ATPD in children. An open trial of haloperidol 7 ATPD has been reported to occur more frequently in women, and a placebo-controlled trial of risperidone 8 are the only 2 rural populations and developing countries. 2,3 ATPD may studies known to the authors. In both the studies, all the persist for 1-3 months depending upon the specific diagnosis as per ICD-10. 4 A study in 2000 reported 2-4 months' duration children developed EPS and were given anticholinergic of ATPD in both developing and industrialized nations. 5 medication. Olanzapine, an atypical antipsychotic, has a similar receptor-binding profile as clozapine but produces less adverse Although ATPD is self-remitting, it has florid symptoms and effects. Olanzapine has been found safe and effective in the it persists long enough to cause impairment to the patient and treatment of schizophrenia, bipolar disorder , pervasive family. Therefore, ATPD should be treated. Although there developmental disorders and T ourette disorder in the are no definite guidelines, it is usually treated by antipsychotic paediatric population. 9 Comparative studies of olanzapine with medication. The use of typical antipsychotic drugs in children haloperidol and risperidone in adults have reported it to be and adolescents (hereafter referred to as children unless better tolerated. Olanzapine produces significantly less EPS specified) is limited because of the development of and patients require less anticholinergic medication than in the case of haloperidol or risperidone. 10 The risk of new-onset tardive dykinesia was much less with olanzapine than with haloperidol or risperidone. 10 To our knowledge, there is no study of olanzapine in A TPD in children. Therefore, this study aimed to examine the efficacy and tolerability of olanzapine in children and adolescents with acute psychosis.

Sample
All children aged 6-16 years consecutively attending the child psychiatry department and presenting with symptoms suggestive of ATPD were assessed initially by a psychiatry postgraduate resident and then jointly with V A or PS. Children-both inpatients and outpatients-with a first episode of ATPD fulfilling the ICD-10 4 criteria (F23) were included in the study . Children on antipsychotic treatment other than olanzapine were not included unless they showed no improvement in 3 weeks on adequate doses or had significant adverse effects. Medication of such children was cross-tapered off in 1week. Children with substance abuse and clinically significant physical illness were excluded. The study was approved by the institutional review board. Informed consent was obtained by parents of all children before their inclusion in the study.

Assessment
VA assessed each patient again in detail, and a consensus diagnosis (VA and PS) was made using the ICD-10 criteria. 4 Weight, blood pressure and pulse rate were recorded at baseline and thereafter weekly throughout the study period of 6 weeks. Routine blood (haemogram) and urine (biochemical and microscopic) investigations were done in all the cases to rule out any physical problem. The patients were assessed on the Brief Psychiatric Rating Scale 11 (BPRS) and Clinical Global Impression 12 (CGI) scale at baseline and thereafter weekly for 6 weeks. Adverse effects were recorded by using the Dosage Record Treatment Emergent Symptom Scale 13 (DOTES) at baseline and weekly thereafter. VA provided the medication and did all the assessments weekly.

Medication
The patients were started on olanzapine 5 mg/day in the first week. Thereafter, the dosage was increased or decreased every week by 2.5-5 mg up to a maximum of 20 mg/day depending upon the clinical improvement or adverse effects. Medications were administered to the patients daily directly under the supervision of one parent to ensure compliance. Concomitant lorazepam 2-4 mg was given during the day or at night for sedation, if needed. Trihexyphenidyl was given for EPS, where necessary.

Statistical analysis
Statistical analysis was done using the paired t-test (two tailed) for comparison of baseline scores to scores at the end of weeks 1 to 6. Intent-to-treat analysis was done. The last observation of each patient was carried forward if the patient had at least 2 weeks of follow-up.

Sample characteristics and diagnosis
Twenty-three children (11 males, 12 females) with a mean age of 14.0±1.3 years (range 11-16 years) were included in the study. Twenty-two (5 inpatients and 17 outpatients) completed the trial while 1 was lost to follow-up after 3 weeks. Twenty patients were studying while 3 were illiterate. A family history of ATPD was present in the mothers of 2 patients and of mania in the sister of 1 patient. The mean duration of illness prior to inclusion in the study was 15.0±10.6 days. Eleven patients (47.8%) were diagnosed as having acute polymorphic psychotic disorder without symptoms of schizophrenia (F23.0), 5 (21.7%) with other A TPD (F 23.8), 3 (13.1%) with acute polymorphic psychotic disorder with symptoms of schizophrenia (F 23.1), 3 (13.1%) with acute schizophrenialike psychotic disorder (F 23.2), and 1 (4.3%) with other acute predominantly delusional psychotic disorders (F 23.3).

Medication dosage
Mean doses of olanzapine were 9.7±1.0, 12.1±2.9 and 12.7±3.9 mg/day at the end of week 2, 4 and 6, respectively . The dose in 1 patient was decreased from 15 mg/day to 12.5 mg/day after 4 weeks due to drowsiness. Concomitant lorazepam was needed in 11 patients (47.8%) a dosage of 2.5±0.9 mg/day in the first week. Nine children (39%) required lorazepam at a dosage of 2.2±1.1 mg/day in the second week. In the next 1-2 weeks, lorazepam was tapered off and it was given to 6 (26%) and 3 patients (13%) in week 3 and 4, respectively. Only 1 patient required trihexyphenidyl. This patient was previously prescribed haloperidol and she developed severe EPS without any improvement in her A TPD. Haloperidol was tapered off in 1 week and she was started on olanzapine. To manage EPS, trihexyphenidyl 6 mg/day was added in the first 2 weeks of the trial and then stopped.

Response to treatment
All the patients showed improvement on olanzapine. The ratings of BPRS at the end of week 6 (Tale 1) showed a significant improvement (t 22 =18.15, p<0.0001) as compared to the baseline. Significant improvement was observed as early as the end of week 2 (t 22 =7.63, p <0.0001). Severity of illness on the CGI scale also showed significant improvement (t 22 =13.65, p<0.0001) at the end of week 6 as compared to baseline. A significant reduction in severity was seen at the end of week 2 (t 22 =7.11, p<0.0001). The ratings of individual

DISCUSSION
This study shows that olanzapine is effective in the treatment of ATPD in children. Recent studies on olanzapine in schizophrenic children and adolescents without resistance to drug treatment have shown that olanzapine is beneficial. [14][15][16] A prospective open trial of olanzapine in 12-17-year-old adolescents with schizophrenia reported significant reduction (p<0.0005) in PANSS total scores and CGI-severity of illness at the end of 8 weeks. The most common adverse effects reported were increased appetite, weight gain and sedation. EPS was observed in 2 patients. 16 These results are comparable with those of our study in which the BPRS total scores and CGI-severity of illness showed a significant reduction (p<0.0001) at the end of 6 weeks. Some common side-effects seen in our study were dryness of mouth, sedation, increased appetite and weight gain. No patient in our study developed EPS.
The remission rate (95.7%) in our study is comparable with or even better than the remission rates in acute psychosis treated with haloperidol 7 (n=27, 10-20 mg/day; 88.9% response) and with risperidone 8 (n=12, 4-6 mg/day; 75% response). Also, olanzapine was well tolerated by all the adolescents in this study. No patient developed EPS and concomitant lorazepam was needed in only 47.8% of patients at a dose of 1-4 mg/day for the initial 1-2 weeks. One may argue that the improvement in these children (47.8%) occurred because of lorazepam. On comparing the improvement beyond week 2 (mean BPRS score 35.6±5.8) in these children ( n= 11), there was a significant improvement at week 4 (mean BPRS score 25.3±5.3, p<0.001) and at week 6 (mean BPRS score 23.0±4.6, p <0.0001) as compared to week 2. So, it can be confidently said that the improvement in these children was because of olanzapine as they improved significantly beyond week 2.
In the studies on haloperidol 7 and risperidone 8 all the patients developed EPS and had to be given trihexyphenidyl. Eleven per cent of patients dropped out of the risperidone study because of EPS. W eight gain was also observed in 55% of patients in the risperidone study. In our study, weight gain was observed in 52% of patients. W eight gain with olanzapine has also been reported in treatment studies in schizophrenic children. 17 Weight gain should not be of much concern in cases of A TPD as long-term maintenance treatment is not required. This weight gain can be controlled by dietary measures during and after treatment and after recovery by physical activity. The dosage of olanzapine in our study (12.7±3.9 mg/day) was also comparable to the dosage of Findling et al. 16 (12.4±5.3 mg/day) and to the usual recommended dose of 10 mg/day for children and adolescents. 18 Therefore, olanzapine may be used in the treatment of paediatric ATPD.

LIMITATION
Limitations of this study are like those of any open and uncontrolled trial. However , the use of placebo in children with ATPD with florid symptoms poses an ethical dilemma. In the risperidone study , 42.8% patients dropped out in the placebo group as they became unmanageable despite being given lorazepam. 8 This study did not monitor the plasma glucose levels. There are a few reports of hyperglycaemia with olanzapine in adolescents. 19 However, treatment emergent hyperglycaemia has been described with typical and atypical antipsychotics and olanzapine is no exception. 20 Also, hyperglycaemia is reversible without any intervention after stoppage of olanzapine. However, caution must be taken while prescribing olanzapine for children with diabetes or those with a family history of diabetes.

CONCLUSION
This preliminary study shows that olanzapine may be a good first-line antipsychotic drug in paediatric A TPD because of its ef fectiveness and tolerability . It has a better side-ef fect profile and patients require less concomitant medication. Also, it has a convenient dosing schedule.
This suggests that further randomized, controlled trials on larger samples are required to confirm the efficacy and safety of olanzapine in paediatric A TPDs.