Add-On Therapy to Risperidonein Schizophrenia (DM)

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

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

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Dextromethorphan

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.

• Study Type: Interventional
• Enrollment (Actual): 161
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• Taiwan
  • Tainan, Taiwan, 704
    • Ru-Band Lu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: dextromethorphan; Research clinical trial of double-blind, stratified randomized, parallel group, double-centre study

Drug: Dextromethorphan; Add-On double-blind study treatment commenced at randomization for 11 weeks while patients were continuing open-label risperidone. Randomization was immediately preceded by a one week open-label Risperidone-Only Treatment period. Patients who were receiving antipsychotics medication(s) at screen other than risperidone alone was withdrawn from previous non-risperidone medication(s) and at the same time commenced risperidone in titrating doses over a week. This Antipsychotic Switch-Over Period occurred between Screen and Risperidone-Only Treatment period. Patients remained hospitalized for at least during the Risperidone-Only treatment Period and first week of Add-On treatment Period.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
positive and negative symptoms in schizophrenia	baseline
positive and negative symptoms in schizophrenia	week1
positive and negative symptoms in schizophrenia	week2
positive and negative symptoms in schizophrenia	week4
positive and negative symptoms in schizophrenia	week6
positive and negative symptoms in schizophrenia	week8
positive and negative symptoms in schizophrenia	week11

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Specific Serum Immunological Parameters	SGOT, SGPT, gamma-GT, BUN and creatinine	baseline
Specific Serum Immunological Parameters		week11
lipid profiles		based line, after treatment

Collaborators and Investigators

• Sponsor: National Cheng-Kung University Hospital

Publications and helpful links

General Publications

• 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. Erratum In: J Neuroimmune Pharmacol. 2012 Dec;7(4):1034. Hong, Jau-Shyong [added].

Study record dates

Study Major Dates

• Study Start: January 1, 2005
• Primary Completion (Actual): December 1, 2008
• Study Completion (Actual): December 1, 2008

Study Registration Dates

• First Submitted: August 23, 2010
• First Submitted That Met QC Criteria: August 24, 2010
• First Posted (Estimate): August 26, 2010

Study Record Updates

• Last Update Posted (Estimate): February 28, 2013
• Last Update Submitted That Met QC Criteria: February 27, 2013
• Last Verified: August 1, 2010

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Respiratory System Agents; Antitussive Agents; Dextromethorphan
• Other Study ID Numbers: DM-Schizo; Taiwan NIH (OTHER_GRANT: DOH98-TD-I-111-DD004)