Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Double-blind, placebo-controlled, crossover trial of D-cycloserine adjuvant therapy for treatment-resistant schizophrenia. D-serine added to antipsychotics for the treatment of schizophrenia. Lamotrigine in treatment-resistant schizophrenia: a randomized placebo-controlled crossover trial. Effect of clozapine and adjunctive high-dose glycine in treatment-resistant schizophrenia. Adjunctive high-dose glycine in the treatment of schizophrenia. Placebo-controlled trial of lamotrigine added to conventional and atypical antipsychotics in schizophrenia. Placebo-controlled trial of glycine added to clozapine in schizophrenia. D-serine added to clozapine for the treatment of schizophrenia. D-cycloserine increases positive symptoms in chronic schizophrenic patients when administered in addition to antipsychotics: a double-blind, parallel, placebo-controlled study. A placebo-controlled crossover trial of D-cycloserine added to clozapine in patients with schizophrenia. Amelioration of negative symptoms in schizophrenia by glycine. Two double-blind placebo-controlled pilot studies of eicosapentaenoic acid in the treatment of schizophrenia. Pharmacotherapy of impaired affect in recovering schizophrenic patients.
Disturbances of N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission may play an important role in the pathophysiology of negative symptoms of schizophrenia. Glycine, a small nonessential amino acid, functions as an obligatory coagonist at NMDA receptors through its action at a strychnine-insensitive binding site on the NMDA receptor complex. Glycine-induced augmentation of NMDA receptor-mediated neurotransmission may thus offer a potentially safe and feasible approach for ameliorating persistent negative symptoms of schizophrenia.
                Twenty-two treatment-resistant schizophrenic patients participated in a double-blind, placebo-controlled, 6-week, crossover treatment trial with 0.8 g/kg per day of glycine added to their ongoing antipsychotic medication. Clinical assessments, including the Brief Psychiatric Rating Scale (BPRS), the Positive and Negative Syndrome Scale (PANSS), the Simpson-Angus Scale for Extrapyramidal Symptoms, and the Abnormal Involuntary Movement Scale, were performed biweekly throughout the study. Clinical laboratory values and amino acid serum levels were monitored.
                Glycine treatment was well tolerated and induced increased glycine (P=.001) and serine (P=.001) serum levels. Glycine administration resulted in (1) a significant (P<.001) 30%+/-16% reduction in negative symptoms, as measured by the PANSS, and (2) a significant (P<.001) 30%+/-18% improvement in the BPRS total scores. The improvement in negative symptoms was unrelated to alterations in extrapyramidal effects or symptoms of depression. Low pretreatment glycine serum levels significantly predicted (r= 0.80) clinical response.
                These findings support hypoglutamatergic hypotheses of schizophrenia and suggest a novel approach for the pharmacotherapy of negative symptoms associated with this illness. Dysfunction of N-methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission may be relevant to the pathogenesis of negative symptoms in schizophrenia. The tuberculostatic compound D-cycloserine (DCS) acts as a partial agonist at the strychnine-insensitive glycine regulatory site on the NMDA receptor complex. Dose-finding trials suggest that DCS doses of 50-100 mg/d may be beneficial in the treatment of negative symptoms in schizophrenia. Nine treatment-resistant chronic schizophrenic patients participated in a double-blind, placebo-controlled, adjuvant treatment trial with 50 mg/d DCS. Between treatment-groups differences in symptom changes were not significant. However, a significant (p<0.05) reduction in negative symptoms was registered during treatment with DCS but not placebo. Greater reductions were registered in patients with lower baseline serum glycine levels (p<0.008). No side effects were registered. These preliminary findings indicate a potential role of DCS in the treatment of negative symptoms in schizophrenia. However, the degree of symptom reduction may be modest, at least among treatment-resistant inpatients. Hypofunction of N-methyl-D-aspartate (NMDA) subtype glutamate receptor has been implicated in the pathophysiology of schizophrenia. D-serine is a full agonist of the glycine site of NMDA receptor, an endogenous cotransmitter enriched in corticolimbic regions and distributed in parallel with NMDA receptor. Supplementation of D-serine may improve the symptoms of schizophrenia.
                Thirty-one Taiwanese schizophrenic patients enrolled in a 6-week double-blind, placebo-controlled trial of D-serine (30 mg/kg/day), which was added to their stable antipsychotic regimens. Of these, 28 completed the trial. Measures of clinical efficacy, side effects, and serum levels of amino acids and D-serine were determined every other week. Wisconsin Card Sorting Test (WCST) was performed at the beginning and end of the trial.
                Patients who received D-serine treatment revealed significant improvements in their positive, negative, and cognitive symptoms as well as some performance in WCST. D-serine levels at week 4 and 6 significantly predicted the improvements. D-serine was well tolerated and no significant side effects were noted.
                The significant improvement with the D-serine further supports the hypothesis of NMDA receptor hypofunction in schizophrenia. Given the effects of D-serine on positive symptoms, a trial of D-serine alone in schizophrenia should be considered. There is no evidence from randomized, controlled trials that demonstrate effectiveness for any pharmacological treatment in clozapine-resistant schizophrenia. Since the introduction of chlorpromazine, all antipsychotics with proven efficacy on positive symptoms have been dopamine antagonists, but recent experimental data suggest that ketamine-induced positive schizophreniform symptoms in healthy subjects can be controlled by a glutamate antagonist lamotrigine. The hypothesis tested was that lamotrigine is more effective than placebo in the treatment of positive schizophrenic symptoms when combined with clozapine.
                Thirty-four hospitalized treatment-resistant patients having chronic schizophrenia participated in a double-blind, placebo-controlled, 14-week, crossover trial where 200 mg/day lamotrigine was gradually added to their ongoing clozapine treatment. Clinical assessments were made by the Positive and Negative Syndrome Scale at the beginning and end of each treatment period.
                In intention-to-treat analysis, lamotrigine treatment was more effective in reducing positive (effect size.7, p =.009) and general psychopathological (effect size.6, p =.030) symptoms, whereas no improvement was observed in negative symptoms.
                These results provide the first evidence from a randomized controlled trial of an effective pharmacological treatment with an anticonvulsant agent in treatment-resistant schizophrenia and indicate that both positive and general psychopathological symptoms in patients with schizophrenia can be controlled by a drug that is not a dopamine antagonist. The results are in line with previous experimental data suggesting that excessive glutamate neurotransmission contributes to the positive symptoms of schizophrenia. The focus of this study was the systematic evaluation of the clinical effects of glycine as an adjunct to the atypical antipsychotic clozapine in the treatment of schizophrenia.
                In a double-blind, placebo-controlled study, 19 patients with chronic, treatment-resistant schizophrenia who were maintained on optimal doses of clozapine (400-1200 mg/day) were administered either 30 g/day of glycine (N=9) or placebo (N=10) for 12 weeks. Clinical evaluations with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Negative Symptoms, and the Simpson-Angus movement scale were completed biweekly.
                The use of glycine as an adjunct to clozapine was not effective in decreasing positive or negative symptoms. In contrast, the patients treated with clozapine without glycine had a 35% reduction in positive symptoms.
                These preliminary data suggest that glycine may interfere with the antipsychotic efficacy of atypical neuroleptics such as clozapine. Glycine is an agonist at brain N-methyl-D-aspartate receptors and crosses the blood-brain barrier following high-dose oral administration. In a previous study, significant improvements in negative and cognitive symptoms were observed in a group of 21 schizophrenic patients receiving high-dose glycine in addition to antipsychotic treatment. This study evaluated the degree to which symptom improvements might be related to alterations in antipsychotic drug levels in an additional group of 12 subjects. Glycine treatment was associated with an 8-fold increase in serum glycine levels, similar to that observed previously. A significant 34% reduction in negative symptoms was observed during glycine treatment. Serum antipsychotic levels were not significantly altered. Significant clinical effects were observed despite the fact that the majority of subjects were receiving atypical antipsychotics (clozapine or olanzapine). As in earlier studies, improvement persisted following glycine discontinuation. Lamotrigine, a novel anticonvulsant drug having modulatory effects on glutamatergic neurotransmission, improves mood and cognition parameters in bipolar disorder. Recent studies suggest that when added to clozapine, lamotrigine treatment may result in significant positive symptoms reductions in schizophrenia. Similar effects were not observed in an open trial in which lamotrigine was used as adjuvant to nonclozapine antipsychotics.
                Thirty-eight treatment-resistant schizophrenia inpatients receiving conventional and atypical antipsychotics enrolled in a 10-week, double-blind, placebo-controlled study, in which they were randomized in a 2:1 ratio to receive adjuvant treatment with lamotrigine, gradually titrated to a 400 mg/day dose, or placebo. Of these, 31 completed the trial. Measures of clinical efficacy and side effects were determined every other week. Serum levels of amino acids were assessed at the beginning and end of the study.
                In primary last observation carried forward analysis, no statistically significant between-group differences were observed; however, the completers' analyses revealed that lamotrigine treatment resulted in significant (p < or = .05) reductions in positive and general psychopathology symptoms, as measured by the Positive and Negative Syndrome Scale. No significant differences in lamotrigine effects were noted between conventional versus atypical antipsychotics. Lamotrigine treatment was well tolerated, and glutamate serum levels remained stable throughout the study.
                These preliminary findings 1) support the hypothesis that lamotrigine adjuvant treatment may improve positive symptoms and general psychopathology in schizophrenia, 2) suggest that beneficial effects may be achieved when lamotrigine is added to both conventional and atypical antipsychotics, and 3) warrant additional, larger scale trials. The purpose of this study was to evaluate the effects of high-dose oral glycine on positive and negative symptoms and cognitive function when added to clozapine in adults with schizophrenia.
                The authors conducted a double-blind, placebo-controlled, parallel-group trial of 60 g/day of glycine added to clozapine for 8 weeks in 30 adults with schizophrenia. Clinical ratings were performed every 2 weeks.
                Twenty-seven patients completed the trial. Glycine augmentation of clozapine produced no statistically significant change in positive or negative symptoms or cognitive functioning. No subjects showed clinically significant worsening of clinical ratings.
                These data, combined with data from previous trials with D-cycloserine and glycine, suggest that agonists at the glycine site may be less effective when combined with clozapine than they are when combined with conventional antipsychotics. D-Serine is a full agonist at the glycine site on the N-methyl-D-aspartate (NMDA) receptor. Previous administration of D-serine to schizophrenic patients taking nonclozapine antipsychotics improved positive, negative, and cognitive symptoms, whereas the partial agonist D-cycloserine improved negative symptoms of patients taking conventional antipsychotics but worsened symptoms in clozapine-treated patients. To study the difference between full and partial agonists at the NMDA receptor glycine site, the clinical effects of adding D-serine to clozapine were assessed.
                In a 6-week double-blind trial, 20 schizophrenic patients received placebo or D-serine (30 mg/kg per day) in addition to clozapine. Clinical efficacy, side effects, and serum levels of D-serine were determined every other week.
                The patients exhibited no improvement with D-serine, nor did their symptoms worsen, as previously reported with D-cycloserine.
                The results suggest either that clozapine may have an agonistic effect on the NMDA system or that clozapine-treated patients do not respond to D-serine. A hypofunction of the glutamatergic system and NMDA receptors in schizophrenia has been hypothesized. Therefore, stimulation of these receptors could be of benefit to patients with schizophrenia. D-cycloserine has been used for this purpose. This study reports the effects of 100 mg D-cycloserine, when added to typical antipsychotics in chronic schizophrenic patients exhibiting prominent negative symptoms, using a placebo-controlled, double-blind, parallel, design. D-cycloserine slightly worsened psychotic symptoms and general psychopathology as compared to placebo. D-cycloserine failed to change negative symptoms and had no effect on extrapyramidal symptoms. The exacerbation of schizophrenic symptoms may be explained by the antagonistic effects of this dose of D-cycloserine at the glycine recognition site of the NMDA receptor due to competition with the endogenous agonist glycine. Another explanation for the increase in psychopathology may be an interaction with the effects of antipsychotics on NMDA mediated neurotransmission. Thus, D-cycloserine in this study did not ameliorate schizophrenic symptoms. However, the fact that they actually worsened suggests that NMDA systems may be involved in the pathogenesis of schizophrenia. Further placebo-controlled studies with lower dosages of D-cycloserine, preferably in drug-free patients, are necessary to evaluate if D-cycloserine is of use for the treatment of patients with schizophrenia. D-Cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor, has previously been shown to improve negative symptoms when added to conventional antipsychotics and, in one preliminary dose-finding study, worsened negative symptoms when added to clozapine.
                Seventeen schizophrenia outpatients treated with clozapine were assigned in random order to 6-week trials of D-cycloserine 50 mg/day and placebo in a crossover design separated by a 1 week placebo washout.
                Eleven patients competed the 13-week study. D-Cycloserine significantly worsened ratings of negative symptoms compared to placebo but did not significantly affect ratings of psychotic symptoms.
                The differing effects of D-cycloserine on negative symptoms when added to clozapine compared to conventional antipsychotics suggests that activation of the glycine recognition site may play a role in clozapine's efficacy for negative symptoms. Phencyclidine induces a psychotomimetic state by blocking neurotransmission at N-methyl-D-aspartic acid (NMDA) receptors. In a double-blind, placebo-controlled fashion, 14 medicated patients with chronic schizophrenia were treated with glycine, a potentiator of NMDA-receptor-mediated neurotransmission. Significant improvement in negative symptoms occurred in the group given glycine but not in the group given placebo, suggesting that potentiation of NMDA-receptor-mediated neurotransmission may represent an effective treatment for neuroleptic-resistant negative symptoms in schizophrenia. Evidence that the metabolism of phospholipids and polyunsaturated fatty acids (PUFA) is abnormal in schizophrenia provided the rationale for intervention studies using PUFA supplementation. An initial open label study indicating efficacy for n-3 PUFA in schizophrenia led to two small double-blind pilot studies. The first study was designed to distinguish between the possible effects of two different n-3 PUFA: eicosapentaenoic acid (EPA) and docohexaenoic acid (DHA). Forty-five schizophrenic patients on stable antipsychotic medication who were still symptomatic were treated with either EPA, DHA or placebo for 3 months. Improvement on EPA measured by the Positive and Negative Syndrome Scale (PANSS) was statistically superior to both DHA and placebo using changes in percentage scores on the total PANSS. EPA was significantly superior to DHA for positive symptoms using ANOVA for repeated measures. In the second placebo-controlled study, EPA was used as a sole treatment, though the use of antipsychotic drugs was still permitted if this was clinically imperative. By the end of the study, all 12 patients on placebo, but only eight out of 14 patients on EPA, were taking antipsychotic drugs. Despite this, patients taking EPA had significantly lower scores on the PANSS rating scale by the end of the study. It is concluded that EPA may represent a new treatment approach to schizophrenia, and this requires investigation by large-scale placebo-controlled trials. Prominent and persistent anxiety, depression, and/or negative features characterize a substantial minority of recovered or residually psychotic schizophrenic outpatients and contribute to poor outcome. Because extrapyramidal side effects of typical neuroleptic medications often resemble such features, we first systematically studied the contribution of extrapyramidal side effects to these problems and their treatment. For patients who remained distressed, controlled trials of supplemental thymoleptics were undertaken.
                In trial 1, 92 distressed (depressed and/or anxious) patients and 36 patients in a defect state (patients with negative symptoms) participated in a double-blind, intramuscular challenge that compared centrally acting benztropine mesylate with peripherally acting glycopyrrolate. In trial 2, 57 distressed patients and 22 patients in a defect state were randomly assigned to a double-blind, neuroleptic medication dose-reduction group. In trial 3, 57 chronically distressed patients who were maintained on a low dose of fluphenazine decanoate were randomly assigned to a supplemental desipramine hydrochloride, lithium carbonate, or placebo group under double-blind conditions for 12 weeks.
                For patients who were already maintained on antiparkinsonian medication, impaired affect was not resolved by additional benztropine. Only distressed patients with a family history of severe mental disorder (often affective) showed improvement with neuroleptic medication dose reduction. Patients in the defect-state group reported less dysphoria on a reduced neuroleptic medication dose, but negative symptoms persisted. Desipramine improved diverse aspects of mood and residual psychoticism, possibly as a prophylaxis against minor affective exacerbations. Depression improved in women only. Lithium positively affected multiple indexes of anxiety and anxious depression.
                Most often, persistent affective impairments are neither resistant extrapyramidal side effects nor characterological traits. Thymoleptics improve the nonphasic, chronic types of anxiety and depression in contrast to the acute, episodic forms, for which little support can be found in the literature.
In general, all glutamatergic drugs appeared to be ineffective in further reducing positive symptoms of the disease when added to the existing antipsychotic treatment. Glycine and D-serine may somewhat improve negative symptoms when added to regular antipsychotic medication, but the results were not fully consistent and data are too few to allow any firm conclusions. Many participants in the included trials were treatment-resistant which may have reduced treatment response. Additional research on glutamatergic mechanisms of schizophrenia is needed.