Augmentation of antipsychotic medication with anticonvulsant in the management of treatment resistant schizophrenia

INTERVENTION: Patients who have a diagnosis of psychotic disorder and having residual symptoms inspite of taking first‐line antipsychotics will be recruited if they meet the conditions for participation. They will be randomly allocated 1:1 to either placebo (inactive pill) + continuing antipsychotic treatment arm or valproate + continuing antipsychotic treatment arm to be treated for a year. The researchers as well as patients will be kept blind to the allocation. Comparing the study medication's effect with dummy pills is the most effective way to prove a treatment's effect in medicine. This is a UK multi‐site study and all patients who start the trial will be analysed even if they discontinue the study medication earlier than planned or if they switch to a second‐line medication called clozapine. The duration of the trial is for 4.5 years including data analysis and publication of report. The trial will include a titration phase for valproate, the study medication, lasting for approximately 2 weeks followed by a maintenance phase for the remaining 50 weeks of the study. At the end of the 52‐week treatment period, subjects will be down titrated over 2 weeks. Outcomes (mental health, well being as well as side effects) will be measured at baseline, 3, 6 and 12 months using standard rating scales and service use will be collected to evaluate cost effectiveness of the study medication. Meetings will be arranged at a site close to where patient's stay and medication will also be dispensed to them. Safety assessments will also be carried out during these visits and patients will be allowed to continue only if they meet a predetermined safety criteria. After patients ha CONDITION: Schizophrenia ; Mental and Behavioural Disorders ; Schizophrenia PRIMARY OUTCOME: Psychotic (positive), negative and general symptom severity in schizophrenia measured using the Positive and Negative Syndrome Scale (PANSS) positive subscale at the 12‐month visit SECONDARY OUTCOME: ; 1. Psychotic (positive) symptom severity in schizophrenia measured using the PANSS positive score at 6 months; 2. Psychotic (positive), negative and general symptom severity in schizophrenia measured using the PANSS at 3, 6 and 12 months; 3. Psychotic (positive), negative and general symptom severity (PANSS) factor scores at baseline at 3, 6 and 12 months; 4. Severity of the patient’s illness measured using the Clinical Global Impression scale (Schizophrenia version) at baseline, 3, 6 & 12‐month follow‐up visits; 5. Aggression levels will be measured using the Modified Overt Aggression Scale at baseline, 3, 6 & 12‐month follow‐up visits; 6. Depression will be measured using the Calgary depression scale for schizophrenia (CDSS) at baseline, 3, 6 & 12‐month follow‐up visits; 7. Manic symptoms will be assessed using Young’s Mania rating scale (YMRS) will be measured at baseline, 3, 6 & 12‐month follow‐up visits; 8. Patient reported outcomes will be evaluated using the Short Warwick‐Edinburgh Well‐being scale (SWEMWBS). It will be measured at baseline, 3, 6‐month and 1‐year time points; 9. Cost effectiveness will be assessed using measures collected at baseline, 3, 6 & 12‐month follow‐up visits: the Client Service Receipt Inventory (CSRI), PANSS and the 36‐item short form health survey (SF‐36); 10. The discontinuation of the intervention will be measured at the 3, 6‐month and 1‐year time points. We will also record the cause of discontinuation under the following categories: (i) lack of efficacy, (ii) adverse effects, (iii) switch to clozapine, (v) lost to follow‐up, (vi) contraindicated with medication that has been added or (vii) personal reasons; 11. We will evaluate on an annual basis the long‐term symptomatic and functional outcomes beyond the 12‐month period primarily using electronic notes to determine service use (admission/crisis/home treatment/other service use) and medical history including HoNOS (Health of the Nation Outcome Scales)to determine outcomes after patients have finished the trial. HoNOS is a global clinical outcomes tool that is routinely collected across all mental health services in the NHS and can be accessed electronically; 12. Number starting clozapine treatment within the study trial period measured using patient records; INCLUSION CRITERIA: 1. Aged 18 and above at the time of consent 2. Adequate command of English to understand the information leaflet 3. Capacity to consent to participation in the study 4. Confirmation of DSM‐5 diagnosis of schizophrenia or schizoaffective disorder using SCID‐5 5. PANSS total symptom severity score > 70 6. At least one PANSS psychotic item rating of at least moderate severity (> 3 on one or more psychotic item rating in PANSS) 7. Received treatment with at least one non‐clozapine antipsychotic drug at adequate dose (as defined by Maudsley guidelines)for a duration of at least 6 weeks and in case of a depot be stable for at least 2 treatment cycles or at least 30 days 8. On a stable dose of antipsychotic treatment for at least 2 weeks in case of oral dosage forms 9. Good adherence to antipsychotic tre