Bipolar Disorder, Schizophrenia
Conditions
Keywords
D-cycloserine, Glycine, Psychosis, Mutation, GABA
Brief summary
The purpose of this study is to assess the efficacy of d-cycloserine (DCS) as an augmentation strategy in two psychotic patients with a triplication (4 copies) of the glycine decarboxylase (GLDC) gene. Subjects will first undergo an eight-week open-label arm of treatment with DCS (50 mg/d) followed by six 6-week double-blind placebo-controlled exposures to DCS or placebo. The length of each double-blind arm is limited to six weeks to minimize the length of symptom exacerbation experienced by the subjects when they are receiving placebo. The randomization scheme will allow two consecutive exposures to DCS, but will not allow two consecutive exposures to placebo, again to minimize the length of any symptom exacerbation. At the end of the open-label DCS trial, the following procedures will be carried out: structural MRI (3T), proton 1H MRS (4T), fMRI (3T), steady-state auditory evoked potentials, and electroretinogram recordings. In addition, 1H MRS (4T) for 2 hours after a single oral dose of a DCS will be assessed. Baseline data on all of these measures were previously obtained as part of a different study registered in clinical trials.gov - NCT01720316). Positive, negative, and affective symptoms and neurocognitive function as well as plasma levels of large neutral and large and small neutral and excitatory amino acids and psychotropic drug levels will be assessed periodically. Pharmaceutical grade DCS) or placebo will be compounded and dispensed by the McLean Hospital Pharmacy. The investigators hypothesize that mutation carriers will have reduced endogenous brain glycine and GABA levels and increased brain glutamate and glutamine levels. DCS administration will increase brain glycine in the two carriers compared to baseline and treatment with glycine (0.8g/kg). The investigators hypothesize reduced activation of magnocellular pathways and abnormal ERPs modulated by NMDA in mutation carriers compared with non-carrier family members and controls. . The investigators hypothesize that DCS, but not placebo, will improve positive, negative and affective symptoms as well as neurocognitive function. The investigators also hypothesize that DCS will improve clinical and cognitive functioning, will partially normalize decreased baseline glycine and GABA and increased glutamate and glutamine, and will partially normalize magnocellular pathway activation and abnormal evoked potentials.
Detailed description
Multiple rare structural variants of relatively recent evolutionary origin are recognized as important risk factors for schizophrenia (SZ) and other neurodevelopmental disorders (e.g., autism spectrum disorders, mental retardation, epilepsy) with odds ratios as high as 7-30. We have found a de novo structural rearrangement on chromosome 9p24.1 in two psychotic patients. One of the genes in this region is the gene encoding glycine decarboxylase (GLDC), which affects brain glycine metabolism. GLDC encodes the glycine decarboxylase or glycine cleavage system P-protein, which is involved in degradation of glycine in glia cells. Carriers of the GLDC triplication would be expected to have low levels of brain Gly, resulting in NMDA receptor-mediated hypofunction, which has been strongly implicated in the pathophysiology of schizophrenia. There is an extensive literature on the effects of NMDA enhancing agents on positive, negative, and depressive symptoms and on neurocognitive function. Although many studies have reported positive results in at least one symptom domain, the results of other studies have been negative or ambiguous. Factors likely to contribute to this variability include: mechanism of action of the agent, compliance, concurrent treatment with first- vs second generation antipsychotic drugs, baseline glycine blood levels, presence/absence of kynurenine pathway metabolic abnormalities and individual differences in brain glycine uptake and metabolism . Genetic variants that impact the synthesis and breakdown of glycine, glutamate, or other modulators of NMDA receptor function are also likely to have significant effects. Although DCS augmentation has shown variable efficacy in patients unselected for having a mutation that would be expected to lower brain glycine levels, the GLDC triplication in the two carriers in this study would be expected to result in unusually low brain glycine levels, supporting its therapeutic potential as an augmentation strategy. Thus, it is important to evaluate the therapeutic efficacy of DCS augmentation in individuals in whom there is a high prior probability of therapeutic benefit and to characterize the neurobiology of this mutation in terms of brain metabolites, brain function, and the pharmacokinetics of glycine metabolism using well-established methods.
Interventions
DRUGD-cycloserine
Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.
DRUGDCS or placebo
Double-blind placebo-controlled exposures to DCS or placebo x 6 weeks. One participant received exposure to DCS x 6 weeks and then received placebo dosing x 6 weeks. The other participant received exposure to placebo dosing x 6 weeks and then DCS x 6 weeks.
Sponsors
University of Minnesota
Mclean Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
34 Years to 62 Years
Healthy volunteers
No
Inclusion criteria
* Carriers of a triplication in the glycine decarboxylase gene
Exclusion criteria
* Not carriers of a triplication in the glycine decarboxylase gene
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Positive and Negative Symptom Scores | Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2 | Positive and Negative Symptom Scale (PANSS) measures positive and negative symptoms of schizophrenia. The sum of ratings for seven positive symptoms is measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.The sum of ratings for seven negative symptoms is measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms. |
| Brief Psychiatric Rating Scale (BPRS) Scores | Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2 | Total BPRS score measures severity of 18 psychiatric symptoms. Each symptom is scored 1-7 with the total score ranging from 18-126. 18 means no symptoms and 126 means very severe symptoms. |
| Clinical Global Impression (CGI) Severity Scores | Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2 | CGI severity scores measure severity of mental illness on a scale of 1-7 where 1 means normal, not at all ill, 2 means borderline mentally ill, 3 means mildly ill, 4 means moderately ill, 5 means markedly ill, 6 means severely ill and 7 means among the most extremely ill patients. |
| Mania Symptom Scores | Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2 | Young Mania Rating Scale (YMRS) measures severity of manic symptoms. The sum of the ratings for 7 symptoms of mania is measured on a scale of 0-4 and the sumof 4 symptoms of mania is measured on a scale of 0-8 to yield a total score ranging from 0-60, with 0 meaning no manic symptoms and 60 meaning severe manic symptoms. |
| Depression Symptom Scores | Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2 | Hamilton Depression Scale (HAM) measures severity of depression symptoms. The sum of the ratings for 9 depression symptoms is measured on a scale of 0-2 with 0 meaning no depression symptoms and 2 meaning some level of severity of that specific symptom. The rating for one depression symptom is measured on a scale of 0-3 with 0 meaning no depression symptoms and 3 meaning a severe level of that specific symptom. The sum of ratings for 11 depression symptoms is measured on a scale of 0-4, with 0 meaning no symptoms and 4 meaning a severe level of that specific symptom. The three sums are added to produce an overall depression rating scale score ranging from 0-65. Higher scores indicate worse depression symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neurocognitive Function | Baseline and Week 8 of open-label DCS treatment | Scores on each of 8 domains of cognitive function (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving, social cognition, overall composite). Scores are T scores ranging from 0-100, with 50 representing the mean for a population based on a normal distribution, standard deviation of 10. Higher scores signify better functioning. |
| Auditory Evoked Potentials - P50 Ratio (P50 S2/S1) (Amplitude) | Baseline and Week 8 of DCS treatment | Auditory evoked potential amplitude: P50 ratio (P50 S2/S1) |
| Brain Glycine/CR Ratio | Baseline and Week 8 of DCS treatment | Proton magnetic resonance spectroscopy at 4T: brain glycine/CR ratio. Participants were assessed at baseline (pre-glycine challenge dose and 60, 80, 100 and 120 minutes post glycine dose) and in week 8 of of open-label DCS treatment: pre-DCS dose, and 60, 80, 100 and 120 minutes post DCS dose. Measured in posterior occipital cortex. |
| Auditory Evoked Potentials in Latency (Msec) | Baseline and Week 8 of DCS treatment | Auditory evoked potential latency: P300 at fz, cz, and pz; N100 at fz and cz; P200 at fz and cz. |
| Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | Baseline and Week 8 of DCS treatment | Auditory evoked potential amplitude: P300 at fz, cz, and pz; N100 at fz and cz; P200 at fz and cz; P50 S1 and S2; mismatch negativity (MMN) at fz and cz. |
| Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared) | Baseline and Week 8 of DCS treatment | Auditory evoked potential gamma: G40 hz phase locking at fz and cz; G30 hz phase locking at fz and cz; G20 hz phase locking at fz and cz |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule for 8 weeks.
D-cycloserine: Both participants received open label D-cycloserine (seromycin), 50 mg/d capsule, x 8 weeks.
Add crossover phase and second OL phase | 2 |
| Total | 2 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 42 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Region of Enrollment United States | 2 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 0 / 2 | 0 / 2 | 0 / 2 | 0 / 2 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 | 0 / 2 | 0 / 2 |
Outcome results
Primary
Brief Psychiatric Rating Scale (BPRS) Scores
Total BPRS score measures severity of 18 psychiatric symptoms. Each symptom is scored 1-7 with the total score ranging from 18-126. 18 means no symptoms and 126 means very severe symptoms.
Time frame: Baseline, 2, 4, & 6 weeks (crossover periods)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 6 weeks BPRS for first intervention | 35 units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 2 weeks BPRS for first intervention | 35 units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 2 weeks BPRS for second intervention | 30 units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 4 weeks BPRS for first intervention | 33 units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 4 weeks BPRS for second intervention | 27 units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | Baseline BPRS for second intervention | 36 units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 6 weeks BPRS for second intervention | 28 units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | Baseline BPRS for first intervention | 29 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 6 weeks BPRS for second intervention | 38 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 6 weeks BPRS for first intervention | 26 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | Baseline BPRS for second intervention | 39 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 2 weeks BPRS for second intervention | 45 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | Baseline BPRS for first intervention | 26 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 2 weeks BPRS for first intervention | 25 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 4 weeks BPRS for second intervention | 45 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 4 weeks BPRS for first intervention | 25 units on a scale |
Primary
Brief Psychiatric Rating Scale (BPRS) Scores
Total BPRS score measures severity of 18 psychiatric symptoms. Each symptom is scored 1-7 with the total score ranging from 18-126. 18 means no symptoms and 126 means very severe symptoms.
Time frame: Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 8 weeks BPRS | 24.5 units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | Baseline BPRS | 37 units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 10 weeks BPRS | NA units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 2 weeks BPRS | 25 units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 12 weeks BPRS | NA units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 4 weeks BPRS | 26 units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 14 weeks BPRS | NA units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 24 weeks BPRS | NA units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 16 weeks BPRS | NA units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 6 weeks BPRS | 24 units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 20 weeks BPRS | NA units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 22 weeks BPRS | NA units on a scale |
| First Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 18 weeks BPRS | NA units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 22 weeks BPRS | 24.5 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 16 weeks BPRS | 28.5 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 20 weeks BPRS | 25 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 24 weeks BPRS | 26.5 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 2 weeks BPRS | 30.5 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 4 weeks BPRS | 28 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 6 weeks BPRS | 25.5 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 8 weeks BPRS | 26 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 10 weeks BPRS | 26.5 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 12 weeks BPRS | 26 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 14 weeks BPRS | 25.5 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | 18 weeks BPRS | 27 units on a scale |
| Second Open Label DCS | Brief Psychiatric Rating Scale (BPRS) Scores | Baseline BPRS | 31.5 units on a scale |
Primary
Clinical Global Impression (CGI) Severity Scores
CGI severity scores measure severity of mental illness on a scale of 1-7 where 1 means normal, not at all ill, 2 means borderline mentally ill, 3 means mildly ill, 4 means moderately ill, 5 means markedly ill, 6 means severely ill and 7 means among the most extremely ill patients.
Time frame: Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 8 weeks CGI | 2 units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 12 weeks CGI | NA units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 14 weeks CGI | NA units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 16 weeks CGI | NA units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 18 weeks CGI | NA units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 24 weeks CGI | NA units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | Baseline CGI | 4 units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 2 weeks CGI | 2 units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 4 weeks CGI | 2 units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 6 weeks CGI | 2 units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 10 weeks CGI | NA units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 20 weeks CGI | NA units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 22 weeks CGI | NA units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 18 weeks CGI | 2.5 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 4 weeks CGI | 2.5 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 12 weeks CGI | 2.5 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 24 weeks CGI | 2.5 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 6 weeks CGI | 2.5 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 16 weeks CGI | 2.5 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 8 weeks CGI | 2.5 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 22 weeks CGI | 2.5 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 20 weeks CGI | 2.5 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 10 weeks CGI | 3 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | Baseline CGI | 2.5 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 14 weeks CGI | 2 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 2 weeks CGI | 2.5 units on a scale |
Primary
Clinical Global Impression (CGI) Severity Scores
CGI severity scores measure severity of mental illness on a scale of 1-7 where 1 means normal, not at all ill, 2 means borderline mentally ill, 3 means mildly ill, 4 means moderately ill, 5 means markedly ill, 6 means severely ill and 7 means among the most extremely ill patients.
Time frame: Baseline, 2, 4, & 6 weeks (crossover periods)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | Baseline CGI for first intervention | 1 units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 4 weeks CGI for second intervention | 2 units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 2 weeks CGI for first intervention | 3 units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 4 weeks CGI for first intervention | 3 units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 6 weeks CGI for first intervention | 3 units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | Baseline CGI for second intervention | 3 units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 2 weeks CGI for second intervention | 2 units on a scale |
| First Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 6 weeks CGI for second intervention | 2 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 6 weeks CGI for second intervention | 3 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 6 weeks CGI for first intervention | 2 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 4 weeks CGI for second intervention | 3 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | Baseline CGI for first intervention | 2 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 2 weeks CGI for second intervention | 3 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 2 weeks CGI for first intervention | 2 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | Baseline CGI for second intervention | 3 units on a scale |
| Second Open Label DCS | Clinical Global Impression (CGI) Severity Scores | 4 weeks CGI for first intervention | 2 units on a scale |
Primary
Depression Symptom Scores
Hamilton Depression Scale (HAM) measures severity of depression symptoms. The sum of the ratings for 9 depression symptoms is measured on a scale of 0-2 with 0 meaning no depression symptoms and 2 meaning some level of severity of that specific symptom. The rating for one depression symptom is measured on a scale of 0-3 with 0 meaning no depression symptoms and 3 meaning a severe level of that specific symptom. The sum of ratings for 11 depression symptoms is measured on a scale of 0-4, with 0 meaning no symptoms and 4 meaning a severe level of that specific symptom. The three sums are added to produce an overall depression rating scale score ranging from 0-65. Higher scores indicate worse depression symptoms.
Time frame: Baseline, 2, 4, & 6 weeks (crossover periods)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| First Open Label DCS | Depression Symptom Scores | 4 weeks HAM for second intervention | 0 units on a scale |
| First Open Label DCS | Depression Symptom Scores | 2 weeks HAM for first intervention | 5 units on a scale |
| First Open Label DCS | Depression Symptom Scores | Baseline HAM for second intervention | 0 units on a scale |
| First Open Label DCS | Depression Symptom Scores | 6 weeks HAM for second intervention | 0 units on a scale |
| First Open Label DCS | Depression Symptom Scores | Baseline HAM for first intervention | 4 units on a scale |
| First Open Label DCS | Depression Symptom Scores | 4 weeks HAM for first intervention | 2 units on a scale |
| First Open Label DCS | Depression Symptom Scores | 6 weeks HAM for first intervention | 10 units on a scale |
| First Open Label DCS | Depression Symptom Scores | 2 weeks HAM for second intervention | 0 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 4 weeks HAM for first intervention | 0 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | Baseline HAM for first intervention | 0 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 6 weeks HAM for first intervention | 0 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 2 weeks HAM for first intervention | 1 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | Baseline HAM for second intervention | 2 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 2 weeks HAM for second intervention | 12 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 6 weeks HAM for second intervention | 2 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 4 weeks HAM for second intervention | 9 units on a scale |
Primary
Depression Symptom Scores
Hamilton Depression Scale (HAM) measures severity of depression symptoms. The sum of the ratings for 9 depression symptoms is measured on a scale of 0-2 with 0 meaning no depression symptoms and 2 meaning some level of severity of that specific symptom. The rating for one depression symptom is measured on a scale of 0-3 with 0 meaning no depression symptoms and 3 meaning a severe level of that specific symptom. The sum of ratings for 11 depression symptoms is measured on a scale of 0-4, with 0 meaning no symptoms and 4 meaning a severe level of that specific symptom. The three sums are added to produce an overall depression rating scale score ranging from 0-65. Higher scores indicate worse depression symptoms.
Time frame: Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| First Open Label DCS | Depression Symptom Scores | Baseline HAM | 5 units on a scale |
| First Open Label DCS | Depression Symptom Scores | 2 weeks HAM | 1.5 units on a scale |
| First Open Label DCS | Depression Symptom Scores | 18 weeks HAM | NA units on a scale |
| First Open Label DCS | Depression Symptom Scores | 4 weeks HAM | 1 units on a scale |
| First Open Label DCS | Depression Symptom Scores | 6 weeks HAM | 0.5 units on a scale |
| First Open Label DCS | Depression Symptom Scores | 8 weeks HAM | 1.5 units on a scale |
| First Open Label DCS | Depression Symptom Scores | 10 weeks HAM | NA units on a scale |
| First Open Label DCS | Depression Symptom Scores | 14 weeks HAM | NA units on a scale |
| First Open Label DCS | Depression Symptom Scores | 20 weeks HAM | NA units on a scale |
| First Open Label DCS | Depression Symptom Scores | 16 weeks HAM | NA units on a scale |
| First Open Label DCS | Depression Symptom Scores | 22 weeks HAM | NA units on a scale |
| First Open Label DCS | Depression Symptom Scores | 24 weeks HAM | NA units on a scale |
| First Open Label DCS | Depression Symptom Scores | 12 weeks HAM | NA units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 24 weeks HAM | 0 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | Baseline HAM | 0.5 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 4 weeks HAM | 1 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 6 weeks HAM | 0 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 8 weeks HAM | 2.5 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 10 weeks HAM | 0 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 18 weeks HAM | 0 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 22 weeks HAM | 0 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 2 weeks HAM | 1 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 12 weeks HAM | 0 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 14 weeks HAM | 0 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 16 weeks HAM | 3.5 units on a scale |
| Second Open Label DCS | Depression Symptom Scores | 20 weeks HAM | 0 units on a scale |
Primary
Mania Symptom Scores
Young Mania Rating Scale (YMRS) measures severity of manic symptoms. The sum of the ratings for 7 symptoms of mania is measured on a scale of 0-4 and the sumof 4 symptoms of mania is measured on a scale of 0-8 to yield a total score ranging from 0-60, with 0 meaning no manic symptoms and 60 meaning severe manic symptoms.
Time frame: Baseline, 2, 4, & 6 weeks (crossover periods)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| First Open Label DCS | Mania Symptom Scores | 2 weeks YMRS for first intervention | 0 units on a scale |
| First Open Label DCS | Mania Symptom Scores | 6 weeks YMRS for first intervention | 0 units on a scale |
| First Open Label DCS | Mania Symptom Scores | Baseline YMRS for first intervention | 1 units on a scale |
| First Open Label DCS | Mania Symptom Scores | 2 weeks YMRS for second intervention | 1 units on a scale |
| First Open Label DCS | Mania Symptom Scores | Baseline YMRS for second intervention | 4 units on a scale |
| First Open Label DCS | Mania Symptom Scores | 4 weeks YMRS for second intervention | 1 units on a scale |
| First Open Label DCS | Mania Symptom Scores | 4 weeks YMRS for first intervention | 0 units on a scale |
| First Open Label DCS | Mania Symptom Scores | 6 weeks YMRS for second intervention | 1 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 4 weeks YMRS for first intervention | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 2 weeks YMRS for first intervention | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | Baseline YMRS for second intervention | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | Baseline YMRS for first intervention | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 6 weeks YMRS for second intervention | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 6 weeks YMRS for first intervention | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 2 weeks YMRS for second intervention | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 4 weeks YMRS for second intervention | 0 units on a scale |
Primary
Mania Symptom Scores
Young Mania Rating Scale (YMRS) measures severity of manic symptoms. The sum of the ratings for 7 symptoms of mania is measured on a scale of 0-4 and the sumof 4 symptoms of mania is measured on a scale of 0-8 to yield a total score ranging from 0-60, with 0 meaning no manic symptoms and 60 meaning severe manic symptoms.
Time frame: Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| First Open Label DCS | Mania Symptom Scores | 14 weeks YMRS | NA units on a scale |
| First Open Label DCS | Mania Symptom Scores | 6 weeks YMRS | 0 units on a scale |
| First Open Label DCS | Mania Symptom Scores | 12 weeks YMRS | NA units on a scale |
| First Open Label DCS | Mania Symptom Scores | 16 weeks YMRS | NA units on a scale |
| First Open Label DCS | Mania Symptom Scores | Baseline YMRS | 2 units on a scale |
| First Open Label DCS | Mania Symptom Scores | 18 weeks YMRS | NA units on a scale |
| First Open Label DCS | Mania Symptom Scores | 10 weeks YMRS | NA units on a scale |
| First Open Label DCS | Mania Symptom Scores | 20 weeks YMRS | NA units on a scale |
| First Open Label DCS | Mania Symptom Scores | 2 weeks YMRS | 1 units on a scale |
| First Open Label DCS | Mania Symptom Scores | 22 weeks YMRS | NA units on a scale |
| First Open Label DCS | Mania Symptom Scores | 8 weeks YMRS | 0 units on a scale |
| First Open Label DCS | Mania Symptom Scores | 24 weeks YMRS | NA units on a scale |
| First Open Label DCS | Mania Symptom Scores | 4 weeks YMRS | 1 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 24 weeks YMRS | 1 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 8 weeks YMRS | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 12 weeks YMRS | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 14 weeks YMRS | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | Baseline YMRS | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 2 weeks YMRS | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 6 weeks YMRS | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 10 weeks YMRS | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 16 weeks YMRS | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 18 weeks YMRS | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 20 weeks YMRS | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 22 weeks YMRS | 0 units on a scale |
| Second Open Label DCS | Mania Symptom Scores | 4 weeks YMRS | 0 units on a scale |
Primary
Positive and Negative Symptom Scores
Positive and Negative Symptom Scale (PANSS) measures positive and negative symptoms of schizophrenia. The sum of ratings for seven positive symptoms is measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.The sum of ratings for seven negative symptoms is measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.
Time frame: Baseline, 2, 4, & 6 weeks (crossover periods)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| First Open Label DCS | Positive and Negative Symptom Scores | Baseline positive for first intervention | 11 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | Baseline negative symptoms for first intervention | 9 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 2 weeks positive for first intervention | 12 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 2 weeks negative for first intervention | 15 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 4 weeks positive for first intervention | 11 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 4 weeks negative for first intervention | 13 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 6 weeks positive for first intervention | 13 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 6 weeks negative for first intervention | 13 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | Baseline positive for second intervention | 13 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 4 weeks negative for second intervention | 11 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 6 weeks positive for second intervention | 9 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | Baseline negative for second intervention | 13 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 2 weeks positive for second intervention | 10 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 2 weeks negative for second intervention | 11 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 4 weeks positive for second intervention | 9 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 6 weeks negative for second intervention | 11 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 2 weeks positive for second intervention | 15 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | Baseline positive for first intervention | 10 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 4 weeks positive for second intervention | 15 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | Baseline negative symptoms for first intervention | 15 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 6 weeks positive for second intervention | 14 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 2 weeks positive for first intervention | 10 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 2 weeks negative for second intervention | 18 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 2 weeks negative for first intervention | 15 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | Baseline positive for second intervention | 15 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 4 weeks positive for first intervention | 10 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 6 weeks negative for second intervention | 18 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 4 weeks negative for first intervention | 15 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | Baseline negative for second intervention | 18 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 6 weeks positive for first intervention | 10 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 4 weeks negative for second intervention | 18 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 6 weeks negative for first intervention | 15 units on a scale |
Primary
Positive and Negative Symptom Scores
Positive and Negative Symptom Scale (PANSS) measures positive and negative symptoms of schizophrenia. The sum of ratings for seven positive symptoms is measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.The sum of ratings for seven negative symptoms is measured on a scale from 7-49 with 7 meaning no symptoms and 49 meaning severe symptoms.
Time frame: Baseline & at 2, 4, 6 & 8 Weeks during open-label phase 1 and every 2 weeks up to 24 weeks during open label phase 2
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| First Open Label DCS | Positive and Negative Symptom Scores | Baseline positive | 14.5 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 8 weeks negative | 12 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 10 weeks negative | NA units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 12 weeks negative | NA units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 14 weeks negative | NA units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 16 weeks positive | NA units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 16 weeks negative | NA units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 18 weeks positive | NA units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 18 weeks negative | NA units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 20 weeks positive | NA units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 22 weeks negative | NA units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 24 weeks positive | NA units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 24 weeks negative | NA units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | Baseline negative | 14.5 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 2 weeks positive | 10 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 2 weeks negative | 12 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 4 weeks positive | 10.5 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 4 weeks negative | 12 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 6 weeks positive | 9 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 6 weeks negative | 12 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 8 weeks positive | 9 units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 10 weeks positive | NA units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 12 weeks positive | NA units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 14 weeks positive | NA units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 20 weeks negative | NA units on a scale |
| First Open Label DCS | Positive and Negative Symptom Scores | 22 weeks positive | NA units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | Baseline positive | 11 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 8 weeks positive | 9.5 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 20 weeks negative | 12 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 8 weeks negative | 12 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | Baseline negative | 14 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 10 weeks negative | 13 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 12 weeks positive | 11 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 6 weeks negative | 13 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 12 weeks negative | 12 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 2 weeks positive | 11 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 14 weeks negative | 12 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 14 weeks positive | 10 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 2 weeks negative | 14 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 16 weeks negative | 12 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 16 weeks positive | 10.5 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 18 weeks positive | 10.5 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 4 weeks positive | 10.5 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 18 weeks negative | 12 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 10 weeks positive | 10.5 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 20 weeks positive | 10.5 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 4 weeks negative | 13.5 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 22 weeks negative | 12 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 22 weeks positive | 9.5 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 24 weeks positive | 10 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 6 weeks positive | 9 units on a scale |
| Second Open Label DCS | Positive and Negative Symptom Scores | 24 weeks negative | 12 units on a scale |
Secondary
Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts)
Auditory evoked potential amplitude: P300 at fz, cz, and pz; N100 at fz and cz; P200 at fz and cz; P50 S1 and S2; mismatch negativity (MMN) at fz and cz.
Time frame: Baseline and Week 8 of DCS treatment
Population: Only one subject had normal hearing, which is required for valid data collection.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | P50 S2: Baseline | 1.23 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | MMN at fz: Baseline | -3.356 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | MMN at cz: Baseline | -4.130 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | P300 at fz: Baseline | -0.635 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | P300 at cz: Baseline | 6.529 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | P300 at pz: Baseline | 5.340 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | N100 at fz: Baseline | -3.926 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | N100 at cz: Baseline | -3.615 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | P200 at fz: Baseline | 1.662 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | P200 at cz: Baseline | 6.591 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | P50 S1: Baseline | 2.759 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | P300 at fz: Week 8 of DCS | 3.030 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | P300 at cz: Week 8 of DCS | 6.810 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | P300 at pz: Week 8 of DCS | 6.620 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | N100 at fz: Week 8 of DCS | -3.260 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | N100 at cz: Week 8 of DCS | -3.940 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | P200 at fz: Week 8 of DCS | 8.200 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | P200 at cz: Week 8 of DCS | 8.160 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | P50 S1: Week 8 of DCS | 1.36 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | P50 S2: Week 8 of DCS | 0.4 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | MMN at fz: Week 8 of DCS | -3.330 microvolts |
| First Open Label DCS | Auditory Evoked Potentials in Amplitude (Degrees Measured in Microvolts) | MMN at cz: Week 8 of DCS | -1.540 microvolts |
Secondary
Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared)
Auditory evoked potential gamma: G40 hz phase locking at fz and cz; G30 hz phase locking at fz and cz; G20 hz phase locking at fz and cz
Time frame: Baseline and Week 8 of DCS treatment
Population: Only one subject had normal hearing, which is required for valid data collection.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| First Open Label DCS | Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared) | G40 hz phase locking at fz: Week 8 of DCS | 0.344 microvolts squared |
| First Open Label DCS | Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared) | G40 hz phase locking at cz: Week 8 of DCS | 0.381 microvolts squared |
| First Open Label DCS | Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared) | G30 hz phase locking at fz: Week 8 of DCS | 0.168 microvolts squared |
| First Open Label DCS | Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared) | G20 hz phase locking at cz: Week 8 of DCS | -0.01 microvolts squared |
| First Open Label DCS | Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared) | G40 hz phase locking at fz: Baseline | 0.135 microvolts squared |
| First Open Label DCS | Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared) | G40 hz phase locking at cz: Baseline | 0.168 microvolts squared |
| First Open Label DCS | Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared) | G30 hz phase locking at fz: Baseline | 0.190 microvolts squared |
| First Open Label DCS | Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared) | G30 hz phase locking at cz: Baseline | 0.163 microvolts squared |
| First Open Label DCS | Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared) | G20 hz phase locking at fz: Baseline | 0.023 microvolts squared |
| First Open Label DCS | Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared) | G20 hz phase locking at cz: Baseline | 0.030 microvolts squared |
| First Open Label DCS | Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared) | G30 hz phase locking at cz: Week 8 of DCS | 0.19 microvolts squared |
| First Open Label DCS | Auditory Evoked Potentials in Gamma Oscillations (the Power Spectrum is Measured in Microvolts Squared) | G20 hz phase locking at fz: Week 8 of DCS | 0.01 microvolts squared |
Secondary
Auditory Evoked Potentials in Latency (Msec)
Auditory evoked potential latency: P300 at fz, cz, and pz; N100 at fz and cz; P200 at fz and cz.
Time frame: Baseline and Week 8 of DCS treatment
Population: Only one subject had normal hearing, which is required for valid data collection.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| First Open Label DCS | Auditory Evoked Potentials in Latency (Msec) | N100 at fz: Baseline | 97.656 msec |
| First Open Label DCS | Auditory Evoked Potentials in Latency (Msec) | P300 at fz: Baseline | 279.297 msec |
| First Open Label DCS | Auditory Evoked Potentials in Latency (Msec) | P300 at cz: Baseline | 279.297 msec |
| First Open Label DCS | Auditory Evoked Potentials in Latency (Msec) | P300 at pz: Baseline | 279.297 msec |
| First Open Label DCS | Auditory Evoked Potentials in Latency (Msec) | N100 at cz: Baseline | 91.797 msec |
| First Open Label DCS | Auditory Evoked Potentials in Latency (Msec) | P200 at fz: Baseline | 197.266 msec |
| First Open Label DCS | Auditory Evoked Potentials in Latency (Msec) | P200 at cz: Baseline | 193.359 msec |
| First Open Label DCS | Auditory Evoked Potentials in Latency (Msec) | P300 at fz: Week 8 of DCS | 294.920 msec |
| First Open Label DCS | Auditory Evoked Potentials in Latency (Msec) | P300 at cz: Week 8 of DCS | 294.000 msec |
| First Open Label DCS | Auditory Evoked Potentials in Latency (Msec) | P300 at pz: Week 8 of DCS | 294 msec |
| First Open Label DCS | Auditory Evoked Potentials in Latency (Msec) | N100 at fz: Week 8 of DCS | 87.9 msec |
| First Open Label DCS | Auditory Evoked Potentials in Latency (Msec) | N100 at cz: Week 8 of DCS | 88.000 msec |
| First Open Label DCS | Auditory Evoked Potentials in Latency (Msec) | P200 at fz: Week 8 of DCS | 212.890 msec |
| First Open Label DCS | Auditory Evoked Potentials in Latency (Msec) | P200 at cz: Week 8 of DCS | 212.000 msec |
Secondary
Auditory Evoked Potentials - P50 Ratio (P50 S2/S1) (Amplitude)
Auditory evoked potential amplitude: P50 ratio (P50 S2/S1)
Time frame: Baseline and Week 8 of DCS treatment
Population: Only one subject had normal hearing, which is required for valid data collection.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| First Open Label DCS | Auditory Evoked Potentials - P50 Ratio (P50 S2/S1) (Amplitude) | P50 ratio: Baseline | 44.51 ratio |
| First Open Label DCS | Auditory Evoked Potentials - P50 Ratio (P50 S2/S1) (Amplitude) | P50 ratio: Week 8 of DCS | 30 ratio |
Secondary
Brain Glycine/CR Ratio
Proton magnetic resonance spectroscopy at 4T: brain glycine/CR ratio. Participants were assessed at baseline (pre-glycine challenge dose and 60, 80, 100 and 120 minutes post glycine dose) and in week 8 of of open-label DCS treatment: pre-DCS dose, and 60, 80, 100 and 120 minutes post DCS dose. Measured in posterior occipital cortex.
Time frame: Baseline and Week 8 of DCS treatment
Population: Data collected only during only one of the open label periods for financial and logistical reasons. Data were collected in week 8 of the first open-label DCS exposure in one subject and in week 8 of the second open-label DCS exposure in the other subject for logistical reasons.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| First Open Label DCS | Brain Glycine/CR Ratio | Week 8 of DCS: 80 minutes | 0.32609 ratio |
| First Open Label DCS | Brain Glycine/CR Ratio | Week 8 of DCS: 100 minutes | 0.32052 ratio |
| First Open Label DCS | Brain Glycine/CR Ratio | Week 8 of DCS: 120 minutes | 0.312155 ratio |
| First Open Label DCS | Brain Glycine/CR Ratio | Baseline | 0.41245 ratio |
| First Open Label DCS | Brain Glycine/CR Ratio | Baseline at 60 minutes | 0.50375 ratio |
| First Open Label DCS | Brain Glycine/CR Ratio | Baseline at 80 minutes | 0.65295 ratio |
| First Open Label DCS | Brain Glycine/CR Ratio | Baseline at 100 minutes | 0.61505 ratio |
| First Open Label DCS | Brain Glycine/CR Ratio | Baseline at 120 minutes | 0.8256 ratio |
| First Open Label DCS | Brain Glycine/CR Ratio | Week 8 of DCS: Baseline | 0.10977 ratio |
| First Open Label DCS | Brain Glycine/CR Ratio | Week 8 of DCS: 60 minutes | 0.248885 ratio |
Secondary
Neurocognitive Function
Scores on each of 8 domains of cognitive function (speed of processing, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving, social cognition, overall composite). Scores are T scores ranging from 0-100, with 50 representing the mean for a population based on a normal distribution, standard deviation of 10. Higher scores signify better functioning.
Time frame: Baseline and Week 8 of open-label DCS treatment
Population: The on DCS data were collected during week 8 of the first open-label portion of the study in one subject and in week 8 of the second open-label portion of the study in the other subject for logistical reasons.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| First Open Label DCS | Neurocognitive Function | Week 8 of open-label DCS Reasoning/Problem Solving | 66.5 T scores |
| First Open Label DCS | Neurocognitive Function | Baseline Processing Speed | 48.5 T scores |
| First Open Label DCS | Neurocognitive Function | Baseline Attention/Vigilance | 44.5 T scores |
| First Open Label DCS | Neurocognitive Function | Baseline Working Memory | 38.5 T scores |
| First Open Label DCS | Neurocognitive Function | Baseline Verbal Learning | 54 T scores |
| First Open Label DCS | Neurocognitive Function | Baseline Visual Learning | 50.5 T scores |
| First Open Label DCS | Neurocognitive Function | Baseline Reasoning/Problem Solving | 52.5 T scores |
| First Open Label DCS | Neurocognitive Function | Baseline Social Cognition | 48 T scores |
| First Open Label DCS | Neurocognitive Function | Baseline Overall Composite Score | 46.5 T scores |
| First Open Label DCS | Neurocognitive Function | Week 8 of open-label DCS Processing Speed | 52.5 T scores |
| First Open Label DCS | Neurocognitive Function | Week 8 of open-label DCS Attention/Vigilance | 47.5 T scores |
| First Open Label DCS | Neurocognitive Function | Week 8 of open-label DCS Working Memory | 50.5 T scores |
| First Open Label DCS | Neurocognitive Function | Week 8 of open-label DCS Verbal Learning | 43.5 T scores |
| First Open Label DCS | Neurocognitive Function | Week 8 of open-label DCS Visual Learning | 54.5 T scores |
| First Open Label DCS | Neurocognitive Function | Week 8 of open-label DCS Social Cognition | 44.5 T scores |
| First Open Label DCS | Neurocognitive Function | Week 8 of open-label DCS Overall Composite Score | 51.5 T scores |