Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders
| Status: | Completed |
|---|---|
| Conditions: | Psychiatric, Psychiatric, Psychiatric, Bipolar Disorder |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 9/20/2017 |
| Start Date: | December 10, 2012 |
| End Date: | May 31, 2017 |
Pilot Study of Glycine Augmentation in Carriers of a Mutation in the Gene Encoding Glycine Decarboxylase
The purpose of this study is to assess the efficacy of oral glycine as an augmentation
strategy in two psychotic patients with a triplication (4 copies) of the gene glycine
decarboxylase (GLDC). Subjects will first undergo a double-blind placebo-controlled clinical
trial in which one 6-week arm will involve glycine (maximum daily dose of 0.8 g/kg,
administered on a TID dosing schedule) and one 6-week arm will involve placebo. A 2-week
period of no treatment will occur between treatment arms. A 6-week period of open-label
glycine (maximum daily dose of 0.8 g/kg, administered on a TID dosing schedule) will follow
the double-blind placebo-controlled clinical trial. Prior to the double-blind
placebo-controlled clinical trial and at the end of the open-label glycine trial, the
following procedures will be carried out: structural MRI (3T), Proton 1H MRS (4T), fMRI (3T),
steady-state visual evoked potentials, and EEG. 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. In addition, 1H MRS (4T) for 2 hours after a single oral dose of a
glycine-containing drink will be assessed at baseline. Pharmaceutical grade glycine powder
(Ajinomoto) or placebo will be dissolved in 20% solution and prepared by the McLean Hospital
Pharmacy.
Because the results of the double-blind placebo-controlled and open-label glycine treatment
arms showed substantial clinical benefit to the participants, the study has been extended to
include six months of chronic open-label glycine in order to determine 1) whether the
clinical benefits achieved within 6 weeks previously recur, 2) the clinical benefits are
lasting, and 3) additional clinical benefits occur with longer exposure. The glycine for this
extension will be provided by Letco Medical.
The investigators hypothesize that mutation carriers will have reduced endogenous brain
glycine and GABA levels and increased brain glutamate and glutamine levels. Glycine
administration will increase brain glycine in the two carriers, but to a lesser extent than
in non-carrier family members and controls.
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 glycine, but not placebo, will improve positive, negative
and affective symptoms as well as neurocognitive function.
The investigators also hypothesize that open-label glycine 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.
strategy in two psychotic patients with a triplication (4 copies) of the gene glycine
decarboxylase (GLDC). Subjects will first undergo a double-blind placebo-controlled clinical
trial in which one 6-week arm will involve glycine (maximum daily dose of 0.8 g/kg,
administered on a TID dosing schedule) and one 6-week arm will involve placebo. A 2-week
period of no treatment will occur between treatment arms. A 6-week period of open-label
glycine (maximum daily dose of 0.8 g/kg, administered on a TID dosing schedule) will follow
the double-blind placebo-controlled clinical trial. Prior to the double-blind
placebo-controlled clinical trial and at the end of the open-label glycine trial, the
following procedures will be carried out: structural MRI (3T), Proton 1H MRS (4T), fMRI (3T),
steady-state visual evoked potentials, and EEG. 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. In addition, 1H MRS (4T) for 2 hours after a single oral dose of a
glycine-containing drink will be assessed at baseline. Pharmaceutical grade glycine powder
(Ajinomoto) or placebo will be dissolved in 20% solution and prepared by the McLean Hospital
Pharmacy.
Because the results of the double-blind placebo-controlled and open-label glycine treatment
arms showed substantial clinical benefit to the participants, the study has been extended to
include six months of chronic open-label glycine in order to determine 1) whether the
clinical benefits achieved within 6 weeks previously recur, 2) the clinical benefits are
lasting, and 3) additional clinical benefits occur with longer exposure. The glycine for this
extension will be provided by Letco Medical.
The investigators hypothesize that mutation carriers will have reduced endogenous brain
glycine and GABA levels and increased brain glutamate and glutamine levels. Glycine
administration will increase brain glycine in the two carriers, but to a lesser extent than
in non-carrier family members and controls.
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 glycine, but not placebo, will improve positive, negative
and affective symptoms as well as neurocognitive function.
The investigators also hypothesize that open-label glycine 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.
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
(Sebat et al. 2009; Malhotra et al. 2011; Heinzen et al. 2010; Weiss et al. 2008; McCarthy et
al. 2009). 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 (Olney & Farber, 1995; Coyle, 2006;
Javitt, 2007).
There is an extensive literature on the effects of NMDA enhancing agents on positive,
negative, and depressive symptoms and on neurocognitive function (see Tsai & Lin, 2010; Lin
et al. 2011 for reviews). Although many studies have reported positive results in at least
one symptom domain (Heresco-Levy et al. 1996, 1999, 2004; Tsai et al. 1998, 1999, 2004, 2006;
Javitt et al. 2001; Goff et al. 1996; Lane et al. 2008), the results of other studies have
been negative or ambiguous (Goff et al. 1999; Evins et al. 2000; Duncan et al. 2004; van
Berckel et al. 1999). 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 (Wonodi et al. 2010; Erhardt et al. 2007) and individual differences
in brain glycine uptake and metabolism (Kaufman et al. 2009; Buchanan et al. 2007). 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 glycine
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 glycine 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 (Kaufman et al.
2009; Prescot et al. 2006; Martinez et al. 2008; Butler et al. 2001; Jensen et al. 2009;
Ongur et al. 2008).
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
(Sebat et al. 2009; Malhotra et al. 2011; Heinzen et al. 2010; Weiss et al. 2008; McCarthy et
al. 2009). 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 (Olney & Farber, 1995; Coyle, 2006;
Javitt, 2007).
There is an extensive literature on the effects of NMDA enhancing agents on positive,
negative, and depressive symptoms and on neurocognitive function (see Tsai & Lin, 2010; Lin
et al. 2011 for reviews). Although many studies have reported positive results in at least
one symptom domain (Heresco-Levy et al. 1996, 1999, 2004; Tsai et al. 1998, 1999, 2004, 2006;
Javitt et al. 2001; Goff et al. 1996; Lane et al. 2008), the results of other studies have
been negative or ambiguous (Goff et al. 1999; Evins et al. 2000; Duncan et al. 2004; van
Berckel et al. 1999). 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 (Wonodi et al. 2010; Erhardt et al. 2007) and individual differences
in brain glycine uptake and metabolism (Kaufman et al. 2009; Buchanan et al. 2007). 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 glycine
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 glycine 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 (Kaufman et al.
2009; Prescot et al. 2006; Martinez et al. 2008; Butler et al. 2001; Jensen et al. 2009;
Ongur et al. 2008).
Inclusion Criteria:
- Triplication of glycine decarboxylase gene
Exclusion Criteria:
- Normal glycine decarboxylase copy number
We found this trial at
1
site
McLean Hospital McLean Hospital is a comprehensive psychiatric hospital committed to providing easy access to...
Click here to add this to my saved trials
