Schizophrenia
Conditions
Keywords
Adult, Cognition, Cycloserine, Dopamine, Female, Glutamic Acid, Human, Male, Receptors, N-Methyl-D-Aspartate, Schizophrenia, Serotonin, Quality of Life, Cycloserine -- *therapeutic use, Dopamine -- blood, Dopamine -- cerebrospinal fluid, Glutamic Acid -- blood, Glutamic Acid -- cerebrospinal fluid, Serotonin -- blood, Serotonin -- cerebrospinal fluid
Brief summary
To characterize further the effects of D-cycloserine augmentation of antipsychotic treatment on negative symptoms, performance on neurocognitive tasks, and on markers for glutamatergic, dopaminergic and serotonergic function in serum and cerebrospinal fluid. To determine if negative symptoms and cognitive function improve over time, if these improvements meaningfully impact quality of life factors, if they correlate with markers of neuronal function, and if subpopulations can be identified according to response. Dysfunction of glutamatergic neuronal systems has recently been implicated in the pathophysiology of schizophrenia based on the finding that non-competitive inhibitors of the NMDA receptor can reproduce in normals the positive symptoms, negative symptoms, and cognitive deficits of schizophrenia. Furthermore, glutamatergic dysfunction may alter forebrain dopaminergic neuronal activity, a system central to the antipsychotic action of typical neuroleptics. It is believed that enhancing NMDA receptor function by systemic treatment with D-cycloserine, a partial agonist at the glycine modulatory site of the NMDA receptor, will reduce symptoms in schizophrenia. Sixty schizophrenic outpatients with prominent, primary negative symptoms are treated with antipsychotic medication and are randomly assigned to D-cycloserine or placebo for a 6-month, fixed-dose trial. The primary outcome measure is the total score on the Scale for Assessment of Negative Symptoms (SANS). A neuropsychological battery, which emphasizes tests sensitive to prefrontal cortical function, is administered. Blood is obtained at several time points and CSF is obtained at Week 8 for assay of concentrations of D-cycloserine, glutamate, HVA, and 5HIAA.
Detailed description
To characterize further the effects of D-cycloserine augmentation of antipsychotic treatment on negative symptoms, performance on neurocognitive tasks, and on markers for glutamatergic, dopaminergic, and serotonergic function in serum and cerebrospinal fluid. To determine if negative symptoms and cognitive function improve over time, if these improvements meaningfully impact quality of life factors, if they correlate with markers of neuronal function, and if subpopulations can be identified according to response. Dysfunction of glutamatergic neuronal systems has recently been implicated in the pathophysiology of schizophrenia based on the finding that non-competitive inhibitors of the NMDA receptor can reproduce in normals the positive symptoms, negative symptoms and cognitive deficits of schizophrenia. Furthermore, glutamatergic dysfunction may alter forebrain dopaminergic neuronal activity, a system central to the antipsychotic action of typical neuroleptics. It is believed that enhancing NMDA receptor function by systemic treatment with D-cycloserine, a partial agonist at the glycine modulatory site of the NMDA receptor, will reduce symptoms in schizophrenia. Sixty schizophrenic outpatients with prominent, primary negative symptoms are treated with antipsychotic medication and are randomly assigned to D-cycloserine or placebo for a 6-month, fixed-dose trial. The primary outcome measure is the total score on the Scale for Assessment of Negative Symptoms (SANS). A neuropsychological battery, which emphasizes tests sensitive to prefrontal cortical function, is administered. Blood is obtained at several time points and CSF is obtained at Week 8 for assay of concentrations of D-cycloserine, glutamate, HVA, and 5HIAA.
Interventions
DRUGD-cycloserine
50 mg/daily by mouth
DRUGPlacebo
50 mg/day of placebo by mouth
Sponsors
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of Schizophrenia as per DSM IV criteria * Have been treated for at least 6 months with any conventional neuroleptic * Have prominent negative symptoms as defined by a total score of 40 or greater on the scale for the assessment of negative symptoms (SANS)
Exclusion criteria
* Active alcohol or drug abuse * Unstable Medical Illness, seizure disorder, or other serious neurological disorder * Pregnant or Nursing * Unable to complete a cognitive battery
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Scale for the Assessment of Negative Symptoms (SANS) | Baseline, Week 4, Week 8 | The slope of SANS total score from baseline to week 8 in the treatment and placebo groups on the scale for the assessment of negative symptoms (SANS) total score. Total SANS scores range from 0-100. The SANS is comprised of 5 subscores: Affective Flattening or Blunting (score range 0-35), Alogia (score range 0-20), Avolition-Apathy (score range 0-15), Anhedonia-Asociality (score range 0-20), and Attention (0-10). For each scale, the higher the score the more prominent the negative symptoms were. The slopes were obtained by plotting the group SANS total score mean for treatment vs. placebo on Baseline, Week 4, and Week 8 and performing a random slopes model. |
Participant flow
Recruitment details
Subjects were adult outpatients recruited from three urban community health centers and two Veteran's Affairs medical centers in the greater Boston area. All eligible participants at these sites were invited to participate by their clinicians.
Pre-assignment details
Sixty subjects met eligibility criteria and provided informed consent, but just 55 completed baseline assessments and were randomized to d-cycloserine or placebo.
Participants by arm
| Arm | Count |
|---|---|
| D-Cycloserine Patients were given 50 mg of D-Cycloserine daily in addition to their treatment as usual with conventional neuroleptics. | 27 |
| Placebo Patients were given 50 mg of placebo daily in addition to their treatment as usual with conventional neuroleptics. | 28 |
| Total | 55 |
Baseline characteristics
| Characteristic | D-Cycloserine | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants | 28 Participants | 55 Participants |
| Age, Continuous | 45.9 Years STANDARD_DEVIATION 7.4 | 47.0 Years STANDARD_DEVIATION 8.6 | 46.5 Years STANDARD_DEVIATION 8 |
| Region of Enrollment United States | 27 participants | 28 participants | 55 participants |
| Sex: Female, Male Female | 3 Participants | 8 Participants | 11 Participants |
| Sex: Female, Male Male | 24 Participants | 20 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Scale for the Assessment of Negative Symptoms (SANS)
The slope of SANS total score from baseline to week 8 in the treatment and placebo groups on the scale for the assessment of negative symptoms (SANS) total score. Total SANS scores range from 0-100. The SANS is comprised of 5 subscores: Affective Flattening or Blunting (score range 0-35), Alogia (score range 0-20), Avolition-Apathy (score range 0-15), Anhedonia-Asociality (score range 0-20), and Attention (0-10). For each scale, the higher the score the more prominent the negative symptoms were. The slopes were obtained by plotting the group SANS total score mean for treatment vs. placebo on Baseline, Week 4, and Week 8 and performing a random slopes model.
Time frame: Baseline, Week 4, Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| D-Cycloserine | Scale for the Assessment of Negative Symptoms (SANS) | -.46 units on a scale/weeks | Standard Error 0.29 |
| Placebo | Scale for the Assessment of Negative Symptoms (SANS) | -.41 units on a scale/weeks | Standard Error 0.31 |