Clinical trial NCT01189006: Add-On Therapy to Risperidonein Schizophrenia
Official title: A Double-blind, Placebo-Controlled, Randomized Study of the Efficacy of Dextromethorphan as Add-On Therapy to Risperidone Versus Risperidone Alone in Patients With Schizophrenia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Schizophrenia
Lead sponsor: National Cheng-Kung University Hospital
Sponsor class: OTHER
First posted: 2010-08-26
Enrollment: 161
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: These results suggest that the DA neuroprotection provided by DM in the inflammation-related neurodegenerative models is not mediated through the NMDA receptor.

Detailed description: Liu et al. (2003) have reported that DM protected dopamine (DA) neurons against inflammation-mediated degeneration. Zhang et al.'s (2004) novel finding was that 1-10 μM DM protected DA neurons against LPS (10 ng/mL)-induced reduction of DA uptake functionally in rat primary mixed mesencephalic neuron-glia cultures. Morphologically, in lipopolysaccharide (LPS)-treated cultures, in addition to the reduction of abundance of DA neurons, the dendrites of the remaining DA neurons were significantly less elaborate than those of controls. In cultures pretreated with DM (10 μM) before LPS stimulation, DA neurons were significantly more numerous and the dendrites less affected. Significant neuroprotective was observed in cultures with DM added up to 60 minutes after the addition of LPS. Thus, DM significantly protects DA neurons not only with pretreatment but also with post-treatment (Zhang et al. 2004). The mechanism of the neuronprotective effect of DM is associated with the inhibition of microglia activation but not with its NMDA receptor antagonist property. Zhang et al. (2005) have examined several N-methyl-D-aspartate (NMDA) receptor antagonists, including MK801, AP5, and memantine. Results from these studies indicate that among these compounds tested there was no correlation between the affinity of NMDA receptor antagonist activity and potency of the neuroprotective on DA neurons. On the contrary, a better correlation was found between the anti-inflammatory potency and the neuron protection. These results suggest that the DA neuroprotection provided by DM in the inflammation-related neurodegenerative models is not mediated through the NMDA receptor. This conclusion is not in conflict with the previous reports, indicating that NMDA receptor blockade is associated with the neuroprotective effect of DM in acute glutamate-induced excitotoxicity models. The above evidences of benefit on auto-immune system with dextromethorphan would support that dextromethorphan as add-on therapy to atypical antipsychotics might be more effective than atypical antipsychotics alone on improvement of both positive and negative symptoms in schizophrenia.

Eligibility criteria: Inclusion Criteria:

1. Male or female patient aged ≧18 and ≦60 years.
2. A diagnosis of schizophrenia or schizoaffective disorder according to DSM-IV criteria made by a specialist in psychiatry.
3. Acute exacerbation of schizophrenia.
4. A total of PANSS score of at least 60 at screen.
5. History of schizophrenia ≦ 15 years (from onset of prodromal symptoms).
6. Signed informed consent by patient or legal representative
7. Patient or a reliable caregiver can be expected to ensure acceptable compliance and visit attendance for the duration of the study.

Exclusion Criteria:

1. Women of childbearing potential not using adequate contraception as per investigator judgement or not willing to comply with contraception for duration of study.
2. Less than a full cycle has lapsed at time of screening following the last injection of a depot antipsychotic
3. Females who are pregnant or nursing.
4. Patient has received dextromethorphan, or other selective cyclo- oxygenase 2 inhibitors, or other anti-inflammatory medication within 1 week prior to first dose of double-blind medication.
5. Axis-I DSM-IV diagnosis other than schizophrenia or schizoaffective disorder.
6. Current evidence of an uncontrolled and/or clinically significant medical condition, e.g., cardiac, hepatic and renal failure that in the judgement of the investigator, would compromise patient safety or preclude study participation.
7. History of intolerance to risperidone or dextromethorphan or other Cox-2 inhibitors.
8. History of sensitivity reaction (e.g., urticaria, angioedema, bronchospasm, severe rhinitis, anaphylactic shock) precipitated by dextromethorphan.
9. Patient has received electroconvulsive therapy (ECT) within 4 weeks prior to first dose of double-blind medication.
10. Diagnosis of or treatment for oesophageal, gastric, pyloric channel, or duodenal ulceration or related complications (bleeding and/or perforation) within 30 days prior to receiving first dose of double-blind medication.
11. Inclusion in another schizophrenia study or study for another indication with psychotropics within the last 30 days prior to start of study.
12. Increase in total SGOT, SGPT, gamma-GT, BUN and creatinine by more than 3X ULN (upper limit of normal).
13. History of idiopathic or drug-induced agranulocytosis.
14. Alcohol, illegal or other substance-abuse within 6 months prior to study start, as defined by DSM-IV criteria.

Primary outcomes:
measure: positive and negative symptoms in schizophrenia
timeFrame: baseline
measure: positive and negative symptoms in schizophrenia
timeFrame: week1
measure: positive and negative symptoms in schizophrenia
timeFrame: week2
measure: positive and negative symptoms in schizophrenia
timeFrame: week4
measure: positive and negative symptoms in schizophrenia
timeFrame: week6
measure: positive and negative symptoms in schizophrenia
timeFrame: week8
measure: positive and negative symptoms in schizophrenia
timeFrame: week11
Secondary outcomes:
measure: Specific Serum Immunological Parameters
timeFrame: baseline
measure: Specific Serum Immunological Parameters
timeFrame: week11
measure: lipid profiles
timeFrame: based line, after treatment
Other outcomes:
Locations:
city: Tainan
country: Taiwan
facility: Ru-Band Lu
Study officials:
affiliation: National Cheng-Kung University Hospital
name: Ru-Band Lu, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Chen SL, Lee SY, Chang YH, Chen SH, Chu CH, Tzeng NS, Lee IH, Chen PS, Yeh TL, Huang SY, Yang YK, Lu RB, Hong JS. Inflammation in patients with schizophrenia: the therapeutic benefits of risperidone plus add-on dextromethorphan. J Neuroimmune Pharmacol. 2012 Sep;7(3):656-64. doi: 10.1007/s11481-012-9382-z. Epub 2012 Jun 23.