Donald C. Goff, M.D. - US grants

DESCRIPTION (Applicant's Abstract): 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. We hypothesized that enhancing NMDA receptor function by systemic treatment with D-cycloserine, a partial agonist at the glycine modulatory site of the NMDA receptor, would reduce symptoms in schizophrenia. We have completed a double-blind dose finding study in a cohort of 10 patients with schizophrenia receiving typical neuroleptics and found significant reduction in negative symptoms and improvement in performance on a frontal cortical cognitive task at a D-cycloserine dose of 50 mg daily. We also have data from 25 patients who have completed an eight-week placebo-controlled parallel group trial of 50 mg D-cycloserine added to typical neuroleptics, which replicate the previous findings. We now propose a larger, six month placebo-controlled trial to characterize further the effects of D-cycloserine augmentation on negative symptoms, performance on neurocognitive tasks, and on markers for glutamatergic, dopaminergic and serotonergic function in serum and cerebrospinal fluid. This study will provide the power to determine if negative symptoms and cognitive function to 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. We will randomly assign 60 schizophrenic outpatients with prominent, primary negative symptoms to D-cycloserine 50 mg or placebo for a six-month, fixed dose trial. The primary outcome measure is the total score on the Scale for Assessment of Negative Symptoms (SANS). We will administer a neuropsychological battery which emphasizes tests sensitive to prefrontal cortical function. Blood will be obtained at several time points and CSF will be obtained at week 8 for assay of concentrations of d-cycloserine, glutamate, HVA and 5HIAA.

The effect of d-cycloserine on negative symptoms (e.g., emotional withdrawal), quality of life and performance of cognitive tests sensitive to prefrontal cortex in 60 outpatients with schizophrenia who meet criteria for primary deficit syndrome and who have clinically significant negative symptoms (measured on the Scale for Assessment of Negative Symptoms (SANS) >40).

excitatory aminoacid; human therapy evaluation; schizophrenia; mental disorder chemotherapy; clozapine; drug screening /evaluation; glutamates; serine; glycine; clinical trials; aspartate; clinical research; blood chemistry; cerebrospinal fluid; human subject;

DESCRIPTION (Applicant's Abstract): Clozapine is more effective for negative symptoms of schizophrenia than conventional neuroleptics, but the neurochemical actions contributing to this superior clinical efficacy remain unclear. Recent evidence points to a role for glutamatergic dysregulation in schizophrenia, as well as important differences between conventional agents and clozapine in effects upon glutamatergic systems. We have shown that D-cycloserine, a partial agonist at the glycine modulatory site of the NMDA receptor, improves negative symptoms when added to conventional agents and worsens negative symptoms when added to clozapine. Another group has demonstrated that high-dose glycine also improves negative symptoms and has provided preliminary evidence suggesting that glycine improves negative symptoms when added to clozapine. Serum concentrations of glycine predicted response to both high-dose glycine and D-cycloserine. These findings led us to the hypothesis that both clozapine and D-cycloserine improve negative symptoms by activation of the glycine modulatory site of the NMDA receptor complex. Because D-cycloserine is a partial agonist, it may act as an antagonist at the glycine site in the presence of clozapine, whereas the full agonist, glycine, would not be expected to worsen negative symptoms in the presence of clozapine. We now propose a placebo-controlled, parallel-group, eight-week, fixed-dose trial of D-cycloserine 50 mg/d and glycine 60 gm/d added to clozapine in 45 patients with schizophrenia. We hypothesize that glycine will produce improvement in negative symptoms and D-cycloserine will produce worsening compared to placebo. We will also determine whether cerebrospinal fluid concentrations of glycine and other relevant amino acids predict response and will measure effects of D-cycloserine and glycine on serum amino acid concentrations. Because assessments are standardized between studies, results from this study can be compared with results from our study of D-cycloserine added to conventional neuroleptic (R01 MH54245).

Candidate: Dr. Goff completed postgraduate training in 1985 and started the Schizophrenia Program of the Massachusetts General Hospital (MGH) with an NIMH "Faculty Scholar Award in Schizophrenia" in 1988. He has focused on augmentation trials for negative symptoms, and over the past five years has conducted a series of studies examining glutamatergic agents and glutamatergic activity of atypical antipsychotics. Dr. Goff has also established a group of ten young investigators working collaboratively to translate recent advances in the neurosciences to the study and treatment of schizophrenia. Environment: Dr. Goo's group has ample space and access to schizophrenia subjects at the Freedom Trail Clinic of the Lindemann Mental Health Center and to a collaborative network of mental health clinics that he has established for recruitment of research subjects in the greater Boston area. He works closely with the MGH Neuroimaging group, the MGH Biostatistics Center, the MGH Amino Acid Laboratory and collaborates with the Transcranial Magnetic Stimulation Research Group at the Beth Israel Hospital and the Brain Imaging Center at McLean Hospital. Dr. Goff is principal investigator for the clinical trials section of the NIMH-funded Neurosciences Center for the Study of Glutamate in Schizophrenia under the leadership of Dr. Joseph Coyle. Dr. Goff has full institutional commitment from Dr. Jerrold Rosenbaum (interim Chief of Psychiatry, MGH) ensuring protected time and resources to accomplish research and mentoring goals. Research: Dr. Goo's research plan involves continuation of his study of glutamatergic agents in schizophrenia and of the role of glutamatergic activity in the therapeutic action of atypical antipsychotics. He will devote the period of the career development award to completing on-going RO1-funded controlled trials of NMDA receptor agonists, initiating trials of new glutamatergic agents (D-serine and an Ampakine) and developing expertise with new research tools and developing collaborations to apply to his research, including neuroimaging, spectroscopy, transcranial magnetic stimulation and genetics. He will also continue his mentoring activities as he guides the career development of ten junior faculty researchers in his group as well as residents and research fellows working on research projects under his direction.

DESCRIPTION (provided by applicant): Treatment of schizophrenia requires long-term interventions that address the range of problems that the illness generates. Continuous receipt of antipsychotic medication is the bedrock on which all other interventions for schizophrenia rest and lack of adherence to a consistent medication regimen characterizes many patients over the long-term. The potential benefits of long acting medication that does not require daily self administration has only been available with first generation antipsychotics. In the United States, these medications have generally been reserved for patients who have demonstrated histories of non-compliance and repeated relapse. There is now a long acting form of one of the second-generation ('atypical') antipsychotics - risperidone microspheres. The availability of a medication that does not share either the side effect burden or the stigma associated with old long acting medications represents a major development in the treatment of schizophrenia. Evaluating the impact of the first available long-acting second-generation is therefore timely, innovative, and of considerable public health significance. With such a formative development for our field, it will be particularly important for clinicians and patients alike to acquire information on relapse prevention that is independent of pharmaceutical support in a manner comparable to prior relapse prevention studies of first generation antipsychotic medications. This eight site collaborative R01 proposes to investigate in an effectiveness, "modern-day" relapse prevention design, whether a long acting second generation medication offers advantages compared to oral second-generation medication. Three hundred four consenting subjects will be randomized to physician's choice oral medication or long acting risperidone, treated for up to two and a half years, and evaluated by masked assessors on measures of psychopathology. Data to be collected will also include time to relapse, level of functioning, service utilization, and medication tolerability. All patients will receive a brief psychoeducational intervention designed to enhance treatment adherence. Even relatively modest delays in relapse and improvement of long term functioning potentially resulting from a long acting second-generation medication can translate into substantial public health benefits.

[unreadable] DESCRIPTION (provided by applicant): Several studies have demonstrated low serum folate concentrations in patients with schizophrenia compared to controls and an association with the common methylenetetrahydrofolate reductase (MTHFR) C677T mutation which results in decreased folate metabolic activity. We have linked negative symptoms and cognitive impairment to low folate serum concentrations and to the MTHFR C677 polymorphism in schizophrenia. In addition, folate 2 mg/d and B12 were recently reported to improve symptoms in 42 schizophrenia patients with elevated homocysteine in a placebo-controlled 12 week trial. This finding is very promising but requires replication and further characterization. We have made several revisions to our study design in response to reviewers' comments, including increasing the sample size to allow for drop-outs, extending the trial to 6 months, and adding B12 to the folate supplementation. Methods: We propose a 24-week, randomized, placebo-controlled, parallel group add-on trial of folate 2 mg/d plus B12 400 micrograms in 144 schizophrenia patients with moderate-or-greater negative symptoms treated with second generation antipsychotics. Our primary endpoint is reduction in negative symptoms. We will also assess cognitive functioning. Potential predictors of response will be assessed, including baseline serum and red blood cell folate concentrations, homocysteine and B12 concentrations, MTHFR C677 polymorphism status and change in folate and B12 concentrations during treatment. Previously-raised ethical concerns about the use of a placebo group will be addressed by excluding patients with elevated plasma homocysteine levels or with megaloblastic anemia, and women who are pregnant. Significance: This study examines two very safe and inexpensive vitamins which serve multiple roles related to brain development and function, including protection against neurotoxicity, synthesis of neurotransmitters and methylation of DNA. Recent findings suggest that folate supplementation may improve negative symptoms and cognitive deficits of schizophrenia-symptoms which confer substantial disability and for which no effective treatments are currently available. This will be the first adequately-powered study to assess efficacy and identify predictors of response. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Depressive symptoms are common early in the course of schizophrenia and are associated with poor quality of life, relapse, and suicidality. As a result, selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed, but their efficacy in first episode patients has not been studied. In a naturalistic study, prodromal patients treated with antidepressants were significantly less likely to progress to schizophrenia. SSRIs release brain derived neurotrophic factor (BDNF) which protects neurons from stress and stimulates neurogenesis. In schizophrenia, BDNF is dysregulated and BDNF genotype has been shown to predict cortical grey matter loss in first episode patients. These findings suggest that SSRI administration might protect against depression, relapse, and disease progression during the early course of the illness. Methods: We propose, in 100 first episode schizophrenia patients, a placebo-controlled, parallel-group, twelve month trial of citalopram added to risperidone treatment plus a psychoeducation protocol designed to enhance compliance and retention. Patients with significant depression or currently treated with an SSRI will be excluded from study and a CBT module targeting depression will be provided if depressive symptoms emerge during the trial. The primary outcome is depressive symptoms analyzed as the area under the curve per unit time. In addition, we will examine suicidality, negative symptoms, cognition, and relapse rates. Biomarkers will include BDNF Val66Met genotype, plasma BDNF concentrations, and gray matter volume to assess a possible relationship between SSRI treatment, enhanced BDNF activity, preservation of cortical gray matter, and improved clinical course. Significance: The evaluation of SSRI treatment for depressive symptoms, suicidal ideation and relapse in first episode patients is of considerable clinical importance. In addition, the potential role of SSRI-induced BDNF release in promoting neurogenesis and improving the course of the illness offers an exciting new direction for the pharmacology of schizophrenia.

DESCRIPTION (provided by applicant): Antipsychotic-resistant delusions are common in schizophrenia and are frequently responsible for incarceration and self injury. Converging evidence from cognitive neuroscience suggests that delusions persist due to an inability to extinguish or unlearn the false belief; a failure to activate ventromedial prefrontal cortex durig memory consolidation appears to play a role in this deficit. D-cycloserine is a highly potent full agonist at a subpopulation of NMDA receptors involved in memory consolidation and robustly enhances memory consolidation in fear extinction models and when combined with CBT in anxiety disorders. We have demonstrated improvement of memory consolidation with D-cycloserine in schizophrenia and, in a pilot trial, demonstrated a large effect on delusional severity and distress when combined with two sessions of CBT employing an alternative beliefs exercise. We now propose a parallel-group, placebo-controlled trial of once-weekly D-cycloserine augmentation of a 12 session CBT treatment for persistent delusions in 60 schizophrenia subjects with follow-up at 3 and 6 months. In addition to assessing and characterizing response of delusions, this study will clarify time course of effect and examine cognitive factors that may mediate D-cycloserine's effect, including enhancement of memory consolidation and of cognitive flexibility. This study will provide data necessary to design and implement a larger, definitive trial that could fundamentally alter the treatment approach to refractory delusions while providing an important clinical test for a compelling new model for delusions.

Increased perfusion of the hippocampal CA1 subfield is a clinical biomarker for early psychosis that also predicts hippocampal volume loss. Converging evidence suggests that CA1 hyperperfusion reflects excessive glutamatergic transmission which drives psychosis and may produce excitotoxic hippocampal injury that is associated with poor outcomes. Antipsychotics reduce hippocampal activity but may worsen hippocampal injury via oxidative stress from increased dopamine release. We recently demonstrated hippocampal volume loss at an annualized mean rate of 6.5% during the first 8 weeks of antipsychotic treatment. Levetiracetam, an anticonvulsant, normalizes excessive glutamatergic and dopaminergic neurotransmission by targeting the synaptic vesicle protein (SVP2A). Levetiracetam is neuroprotective in animal and human models of hippocampal hyperactivity. We hypothesize that levetiracetam will protect against hippocampal volume loss and improve clinical outcomes in early psychosis by reducing excessive glutamate and dopamine transmission. Approach: We will establish target engagement and dose selection by measuring the effects of levetiracetam 185 mg and 500 mg on hippocampal perfusion in a placebo-controlled trial in 24 medication- naïve individuals with first episode psychosis. We will then study the optimal levetiracetam dose added to antipsychotic in a 12-week placebo-controlled trial in 84 medication naïve individuals with first episode psychosis. We will examine whether levetiracetam prevents hippocampal volume loss and improves clinical symptoms and cognition and will explore potential mediators and modulators of effect. Significance: By correcting a fundamental dysregulation of hippocampal neurotransmission, we believe levetiracetam will improve initial treatment response in first episode psychosis and fundamentally change the course of illness.

SUMMARY Hippocampal memory circuits are strongly implicated in the formation and persistence of delusions. In particular, the dentate gyrus (DG) and the CA1 subfield are vulnerable to early developmental stressors that are risk factors for schizophrenia; postmortem evidence points to deficits in inhibitory input and in neurogenesis. We hypothesize that delusions result from aberrant associative memory formation due to impaired functioning of DG/CA3 subfields and persist due to a failure to update false beliefs with new episodic information due to reduced mnemonic prediction error signaling in CA1 and reduced post-encoding consolidation of newly formed memories. Because antipsychotics target hippocampal memory circuits, it is important to study these circuits in unmedicated subjects. We propose to apply three task-based fMRI paradigms to examine early mnemonic associative processing, prediction error, and plasticity of circuits associated with encoding and retrieval in three experiments, each including 50 first episode nonaffective psychosis (FEP) subjects and 50 healthy matched controls. The medication-naïve FEP subjects will be re- studied after 8 weeks of antipsychotic treatment to examine the relationship between medication effects on delusional severity and on hippocampal memory circuits. Imaging will also be repeated after 8 weeks in healthy controls to assess learning effects. The first paradigm, a behavioral pattern separation task, has not previously been studied in medication-naïve first episode psychosis. The paradigms for assessment of CA1 activation during prediction error and of plasticity of connectivity between hippocampal subfields, the ventral tegmental area dopamine neurons and cortical regions were recently developed and validated by Dr. Davachi's team in healthy subjects; we have demonstrated feasibility of these paradigms in schizophrenia subjects. The proposed project will advance our understanding of circuits involved in delusions and their pharmacologic response, will provide validated imaging biomarkers for clinical studies and will identify new targets for treatment development.

While most people with psychosis are not dangerous and most violence is committed by non-psychotic people, people with psychotic disorders are at increased risk for violence, and violence is associated with worse outcomes and increased stigma. Therefore, decreasing violence risk in psychosis is clinically relevant and has important public health implications. Several clinical studies suggest that clozapine is superior to other antipsychotic medications in reducing violence or aggression. However, there were numerous limitations of these studies including that most of them were observational and non-randomized, included small sample sizes, or focused on hostility, non-physical aggression, or self-harm, rather than violent acts. Further, the majority of these trials were not generalizable to outpatient, community settings. No large effectiveness study has examined the effects of clozapine on violent behavior in community settings. We propose a randomized, parallel-group, 24-week, open-label, single (rater)-blind, 7-site clinical trial to examine the effects of treatment with clozapine vs. treatment as usual (TAU) on the risk of violent acts in 280 individuals with schizophrenia at high risk for violence. This trial will be a collaboration of 7 sites, coordinated by the New York State Psychiatric Institute. The 6 additional collaborating sites contribute unique expertise and will ensure an adequate sample size for this trial. Our primary effectiveness outcome is time to violent acts as measured by the MacArthur Community Violence Interview (MCVI). We will also explore the effects of clozapine on the Point Subtraction Aggression Paradigm. While many factors may contribute to violent behavior in individuals with schizophrenia, including positive symptoms, psychopathy, impulsivity, and substance use, evidence suggests that the final common pathway for many of these disparate causal influences likely runs through behaviors captured by the Excitement Factor of the Positive and Negative Syndrome Scale (i.e., a composite of the scores of excitement, uncooperativeness, poor impulse control, and hostility). Importantly, our target (the excitement factor of the PANSS) has been validated to measure excitement-like symptoms in clinical trials in schizophrenia, is sensitive to treatment, has been linked to the neurobiology of violence in spectroscopy and PET studies, and differentiates clozapine from other antipsychotic drugs. We will also explore the effects of clozapine vs. TAU on positive symptoms (e.g., persecutory delusions) and alcohol and substance use, and how these effects influence the risk for violent acts. To enhance the safe implementation of this study in this vulnerable population at risk of violent behaviors, we will implement clinical safety and treatment engagement protocols that rely upon standard personnel and that will be readily generalizable. This trial will provide guidance on the use of clozapine for violence in community settings and will definitively test hypotheses regarding mechanisms of its anti-violence effects. The results will be immediately relevant to practice and will impact public health because there is currently no standard approach for the treatment of violence in schizophrenia.