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JAMA Psychiatry Dec 2022The antidepressant effects of transcranial magnetic stimulation protocols for major depressive disorder (MDD) are thought to depend on synaptic plasticity. The... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
The antidepressant effects of transcranial magnetic stimulation protocols for major depressive disorder (MDD) are thought to depend on synaptic plasticity. The theta-burst stimulation (TBS) protocol synaptic plasticity is known to be N-methyl-D-aspartate (NMDA)-receptor dependent, yet it is unknown whether enhancing NMDA-receptor signaling improves treatment outcomes in MDD.
OBJECTIVE
To test whether low doses of the NMDA-receptor partial-agonist, D-cycloserine, would enhance intermittent TBS (iTBS) treatment outcomes in MDD.
DESIGN, SETTING, AND PARTICIPANTS
This was a single-site 4-week, double-blind, placebo-controlled, randomized clinical trial conducted from November 6, 2019, to December 24, 2020, including 50 participants with MDD. Participants were recruited via advertisements and referral. Inclusion criteria were as follows: age 18 to 65 years with a primary diagnosis of MDD, a major depressive episode with score of 18 or more on the 17-item Hamilton Depression Rating Scale, a Young Mania Rating Scale score of 8 or less, and normal blood work (including complete blood cell count, electrolytes, liver function tests, and creatinine level).
INTERVENTIONS
Participants were randomly assigned 1:1 to either iTBS plus placebo or iTBS plus D-cycloserine (100 mg) for the first 2 weeks followed by iTBS without an adjunct for weeks 3 and 4.
MAIN OUTCOMES AND MEASURES
The primary outcome was change in depressive symptoms as measured by the Montgomery-Åsberg Depression Rating Scale (MADRS) at the conclusion of treatment. Secondary outcomes included clinical response, clinical remission, and Clinical Global Impression (CGI) scores.
RESULTS
A total of 50 participants (mean [SD] age, 40.8 [13.4] years; 31 female [62%]) were randomly assigned to treatment groups: iTBS plus placebo (mean [SD] baseline score, 30.3 [4.2]) and iTBS plus D-cycloserine (mean [SD] baseline score, 30.4 [4.5]). The iTBS plus D-cycloserine group had greater improvements in MADRS scores compared with the iTBS plus placebo group (mean difference, -6.15; 95% CI, -2.43 to -9.88; Hedges g = 0.99; 95% CI, 0.34-1.62). Rates of clinical response were higher in the iTBS plus D-cycloserine group than in the iTBS plus placebo group (73.9% vs 29.3%), as were rates of clinical remission (39.1% vs 4.2%). This was reflected in lower CGI-severity ratings and greater CGI-improvement ratings. No serious adverse events occurred.
CONCLUSIONS AND RELEVANCE
Findings from this clinical trial indicate that adjunctive D-cycloserine may be a promising strategy for enhancing transcranial magnetic stimulation treatment outcomes in MDD using iTBS requiring further investigation.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03937596.
Topics: Female; Humans; Adult; Adolescent; Young Adult; Middle Aged; Aged; Depressive Disorder, Major; Cycloserine; Transcranial Magnetic Stimulation
PubMed: 36223114
DOI: 10.1001/jamapsychiatry.2022.3255 -
Clinical Infectious Diseases : An... Sep 2022The ability of antituberculosis drugs to cross the blood-brain barrier and reach the central nervous system is critical to their effectiveness in treating tuberculosis...
BACKGROUND
The ability of antituberculosis drugs to cross the blood-brain barrier and reach the central nervous system is critical to their effectiveness in treating tuberculosis meningitis (TBM). We sought to fill a critical knowledge gap by providing data on the ability of new and repurposed antituberculosis drugs to penetrate into the cerebrospinal fluid (CSF).
METHODS
We conducted a clinical pharmacology study among patients treated for TBM in Tbilisi, Georgia, from January 2019 until January 2020. Serial serum and CSF samples were collected while patients were hospitalized. CSF was collected from routine lumbar punctures with the timing of the lumbar puncture alternating between 2 and 6 hours to capture early and late CSF penetration.
RESULTS
A total of 17 patients treated for TBM (8 with confirmed disease) were included; all received linezolid, with a subset receiving cycloserine (5), clofazimine (5), delamanid (4), and bedaquiline (2). All CSF measurements of bedaquiline (12), clofazimine (24), and delamanid (19) were below the limit of detection. The median CSF concentrations of cycloserine at 2 and 6 hours were 15.90 and 15.10 µg/mL with adjusted CSF/serum ratios of 0.52 and 0.66. CSF concentrations of linezolid were 0.90 and 3.14 µg/mL at 2 and 6 hours, with adjusted CSF/serum ratios of 0.25 and 0.59, respectively. CSF serum linezolid concentrations were not affected by rifampin coadministration.
CONCLUSIONS
Based on moderate to high CSF penetration, linezolid and cycloserine may be effective drugs for TBM treatment, whereas the utility of bedaquiline, delamanid, and clofazimine is uncertain given their low CSF penetration.
Topics: Antitubercular Agents; Clofazimine; Cycloserine; Humans; Linezolid; Mycobacterium tuberculosis; Tuberculosis, Meningeal
PubMed: 34849645
DOI: 10.1093/cid/ciab992 -
International Journal of Infectious... Apr 2021Cycloserine, or its structural analogue terizidone, has been associated with neuropsychiatric toxicity (psychosis, depression, and neuropathy). Prospective clinical data...
BACKGROUND
Cycloserine, or its structural analogue terizidone, has been associated with neuropsychiatric toxicity (psychosis, depression, and neuropathy). Prospective clinical data on the incidence of and risk factors for neuropsychiatric toxicity in TB patients treated with cycloserine are limited.
METHODS
A prospective evaluation of neuropsychiatric toxicity was performed using validated screening tools in patients with multidrug-resistant tuberculosis treated with terizidone. Cox proportional hazard modelling was performed to explore the effects of clinical variables and measures of cycloserine pharmacokinetics in plasma.
RESULTS
A total 144 participants were recruited: 86 were male and 58 were female; their median age was 35.7 years and 91 (63%) were HIV-infected. Fifty-five (38%) participants developed at least one neuropsychiatric event (30 cases per 100 person-months): 50 (35%) neuropathy, 14 (10%) depression, and 11 (8%) psychosis. Neuropathy was independently associated with cycloserine clearance ((adjusted hazard ratio 0.34 (aHR), P = 0.03)) and high-dose pyridoxine (200 mg vs 150 mg daily, aHR: 2.79, P = 0.01).
CONCLUSIONS
A high incidence of early neuropsychiatric toxicity was observed in this cohort of patients treated with terizidone. Cycloserine clearance and higher doses of pyridoxine are associated with incident or worsening peripheral neuropathy.
Topics: Adult; Antibiotics, Antitubercular; Cycloserine; Depression; Female; HIV Infections; Humans; Incidence; Isoxazoles; Male; Middle Aged; Oxazolidinones; Peripheral Nervous System Diseases; Prospective Studies; Psychoses, Substance-Induced; Risk Factors; Tuberculosis, Multidrug-Resistant
PubMed: 33684562
DOI: 10.1016/j.ijid.2021.03.001 -
The International Journal of... Apr 2016D-Cycloserine, known from tuberculosis therapy, has been widely introduced to neuropsychiatric studies, since its central active mechanism as a partial NMDA-agonist has... (Review)
Review
D-Cycloserine, known from tuberculosis therapy, has been widely introduced to neuropsychiatric studies, since its central active mechanism as a partial NMDA-agonist has been found. In this review, we evaluate its therapeutic potential in neuropsychological disorders and discuss its pitfalls in terms of dosing and application frequency as well as its safety in low-dose therapy. Therefore, we identified 91 clinical trials by performing a Medline search. We demonstrate in part preliminary but increasing evidence that D-cycloserine may be effective in various psychiatric diseases, including schizophrenia, anxiety disorders, addiction, eating disorders, major depression, and autism as well as in neurological diseases, including dementia, Alzheimer's disease, and spinocerebellar degeneration. D-Cycloserine in low-dose therapy is safe, but there is still a need for new drugs with higher specificity to the different N-methyl-D-aspartate-receptor subunits.
Topics: Animals; Cycloserine; Excitatory Amino Acid Agonists; Humans; Mental Disorders; Nervous System Diseases; Psychotropic Drugs; Receptors, N-Methyl-D-Aspartate
PubMed: 26364274
DOI: 10.1093/ijnp/pyv102 -
The Cochrane Database of Systematic... Feb 2021Symptoms of autism spectrum disorder (ASD) have been associated, in part, with the dysfunction of N-methyl-D-aspartate (NMDA) glutamate receptors at excitatory synapses...
BACKGROUND
Symptoms of autism spectrum disorder (ASD) have been associated, in part, with the dysfunction of N-methyl-D-aspartate (NMDA) glutamate receptors at excitatory synapses and glutamate abnormalities. Medications related to glutamatergic neurotransmission, such as D-cycloserine - which is a partial agonist of the NMDA glutamate receptor - are potential treatment options for the core features of ASD. However, the potential effect of D-cycloserine on the social and communication skills deficits of individuals with ASD has not been thoroughly explored and no systematic reviews of the evidence have been conducted.
OBJECTIVES
To assess the efficacy and adverse effects of D-cycloserine compared with placebo for social and communication skills in individuals with ASD.
SEARCH METHODS
In November 2020, we searched CENTRAL, MEDLINE, Embase, six other databases and two trials registers. We also searched the reference lists of relevant publications and contacted the authors of the included study, Minshawi 2016, to identify any additional studies. In addition, we contacted pharmaceutical companies, searched manufacturers' websites and sources of reports of adverse events. SELECTION CRITERIA: All randomised controlled trials (RCTs) of any duration and dose of D-cycloserine, with or without adjunct treatment, compared to placebo in individuals with ASD.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected studies for inclusion, extracted relevant data, assessed the risk of bias, graded the certainty of the evidence using the GRADE approach, and analysed and evaluated the data. We provide a narrative report of the findings as only one study is included in this review.
MAIN RESULTS
We included a single RCT (Minshawi 2016) funded by the United States Department of Defense. It was conducted at two sites in the USA: Indiana University School of Medicine and Cincinnati Children's Hospital Medical Centre. In the included study, 67 children with ASD aged between 5 and 11 years were randomised to receive either 10 weeks (10 doses) of (50 mg) D-cycloserine plus social skills training, or placebo plus social skills training. Randomisation was carried out 1:1 between D-cycloserine and placebo arms, and outcome measures were recorded at one-week post-treatment. The 'risk of bias' assessment for the included study was low for five domains and unclear for two domains. The study (67 participants) reported low certainty evidence of little to no difference between the two groups for all outcomes measured at one week post-treatment: social interaction impairment (mean difference (MD) 3.61 (assessed with the Social Responsiveness Scale), 95% confidence interval (CI) -5.60 to 12.82); social communication impairment (MD -1.08 (measured using the inappropriate speech subscale of the Aberrant Behavior Checklist (ABC)), 95% CI -2.34 to 0.18); restricted, repetitive, stereotyped patterns of behaviour (MD 0.12 (measured by the ABC stereotypy subscale), 95% CI -1.71 to 1.95); serious adverse events (risk ratio (RR) 1.11, 95% CI 0.94 to 1.31); non-core symptoms of ASD (RR 0.97 (measured by the Clinical Global Impression-Improvement scale), 95% CI 0.49 to 1.93); and tolerability of D-cycloserine (RR 0.32 (assessed by the number of dropouts), 95% CI 0.01 to 7.68). AUTHORS' CONCLUSIONS: We are unable to conclude with certainty whether D-cycloserine is effective for individuals with ASD. This review included low certainty data from only one study with methodological issues and imprecision. The added value of this review compared to the included study is we assessed the risk of bias and evaluated the certainty of evidence using the GRADE approach. Moreover, if we find new trials in future updates of this review, we could potentially pool the data, which may either strengthen or decrease the evidence for our findings.
Topics: Autism Spectrum Disorder; Child; Child, Preschool; Communication; Cycloserine; Female; Humans; Indiana; Male; Multicenter Studies as Topic; Ohio; Patient Dropouts; Placebos; Randomized Controlled Trials as Topic; Social Skills; Stereotyped Behavior
PubMed: 33583058
DOI: 10.1002/14651858.CD013457.pub2 -
The Cochrane Database of Systematic... May 2015A significant number of patients who suffer with anxiety and related disorders (that is post-traumatic stress disorder (PTSD), social anxiety disorder (SAnD), panic... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
A significant number of patients who suffer with anxiety and related disorders (that is post-traumatic stress disorder (PTSD), social anxiety disorder (SAnD), panic disorder with or without agoraphobia (PD), specific phobia (SPh) and obsessive compulsive disorder (OCD)) fail to respond optimally to first-line treatment with medication or cognitive and behavioural therapies. The addition of d-cycloserine (DCS) to cognitive and behavioural therapies may improve treatment response by impacting the glutamatergic system. This systematic review aimed to investigate the effects of adding DCS to cognitive and behavioural therapies by synthesising data from relevant randomised controlled trials and following the guidelines recommended by Cochrane.
OBJECTIVES
To assess the effect of DCS augmentation of cognitive and behavioural therapies compared to placebo augmentation of cognitive and behavioural therapies in the treatment of anxiety and related disorders. Additionally, to assess the efficacy and tolerability of DCS across different anxiety and related disorders.
SEARCH METHODS
This review fully incorporates studies identified from a search of the Cochrane Depression, Anxiety and Neurosis Controlled Trials Register (CCDANCTR) to 12 March 2015. This register includes relevant randomised controlled trials (RCTs) from: the Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date), PsycINFO (1967 to date), the World Health Organization's trials portal (ICTRP) and ClinicalTrials.gov . Reference lists from previous meta-analyses and reports of RCTs were also checked. No restrictions were placed on language, setting, date or publication status.
SELECTION CRITERIA
All RCTs of DCS augmentation of cognitive and behavioural therapies versus placebo augmentation of cognitive and behavioural therapies for anxiety and related disorders were included.
DATA COLLECTION AND ANALYSIS
Two authors (RO and TA) independently assessed RCTs for eligibility and inclusion, extracted outcomes and risk of bias data and entered these into a customised extraction form. Investigators were contacted to obtain missing data. In addition, data entry and analysis were performed by two review authors (KSW and HB).
MAIN RESULTS
Twenty-one published RCTs, with 788 participants in outpatient settings, were included in the review. Sixteen studies had an age range of 18 to 75 years, while four investigated paediatric populations aged 8 to 17 years and one included children, adolescents and adults. The 21 RCTs investigated OCD (number of RCTs (N) = 6), PTSD (N = 5), SAnD (N = 5), SPh (N = 3) and PD (N = 2). Most information from the studies was rated as having either low risk or unclear risk of bias.There was no evidence of a difference between DCS augmentation of cognitive and behavioural therapies and placebo augmentation of cognitive and behavioural therapies for the treatment of anxiety and related disorders in adults at the endpoint (treatment responders, N = 9, risk ratio (RR) 1.10; 95% confidence interval (CI) 0.89 to 1.34; number of participants (n) = 449; low quality evidence) and between 1 and 12 months follow-up (N = 7, RR 1.08; 95% CI 0.90 to 1.31; n = 383). DCS augmentation of cognitive and behavioural therapies was not superior to placebo augmentation of cognitive and behavioural therapies for children and adolescents, both at the endpoint (N = 4, RR 1.01; 95% CI 0.78 to 1.31; n = 121; low quality evidence) and between 3 and 12 months follow-up (N = 3, RR 0.86; 95% CI 0.67 to 1.09; n = 91).There was no evidence of a difference in treatment acceptability for DCS augmentation of cognitive and behavioural therapies compared with placebo augmentation of cognitive and behavioural therapies in adults (N = 16, RR 0.88; 95% CI 0.61 to 1.25; n = 740), nor in children and adolescents (N = 4, RR 0.90; 95% CI 0.17 to 4.69; n = 131). These conclusions were based on moderate quality evidence for adults, and very low quality evidence for children and adolescents. Although the observed difference was small, it is noteworthy that there was a high efficacy of exposure-based therapies alone in the included trials. Due to the limited number of studies, subgroup analysis of moderating factors for clinical and methodological effect could not take place.
AUTHORS' CONCLUSIONS
This review found no evidence of a difference between DCS augmentation of cognitive and behavioural therapies and placebo augmentation of cognitive and behavioural therapies for treating anxiety and related disorders in children, adolescents and adults. These findings are based on low quality evidence from heterogenous studies with small sample sizes and incomplete data for clinical response, which precludes us from drawing conclusions on the use of DCS augmentation of cognitive and behavioural therapies at this stage. Given there is some promising preliminary data from individual studies, further research is necessary to assess DCS compared with placebo augmentation of cognitive and behavioural therapies, and determine mechanisms of action as well as magnitude of effect in anxiety and related disorders.
Topics: Adolescent; Adult; Aged; Anxiety Disorders; Child; Cognitive Behavioral Therapy; Combined Modality Therapy; Cycloserine; Humans; Middle Aged; Randomized Controlled Trials as Topic
PubMed: 25957940
DOI: 10.1002/14651858.CD007803.pub2 -
Antimicrobial Agents and Chemotherapy Dec 2020Treatment outcomes among multidrug-resistant tuberculosis (MDR-TB) patients receiving ethambutol, cycloserine, or terizidone as part of a standardized regimen were...
Treatment outcomes among multidrug-resistant tuberculosis (MDR-TB) patients receiving ethambutol, cycloserine, or terizidone as part of a standardized regimen were compared, determining occurrence of serious adverse drug events (SADEs). Newly diagnosed adult MDR-TB patients were enrolled between 2000 and 2004, receiving a standardized multidrug regimen for 18 to 24 months, including ethambutol, cycloserine, or terizidone. Cycloserine and terizidone were recorded individually. SADEs and factors associated with culture conversion and unfavorable treatment outcomes (default, death, treatment failure) were determined. Of 858 patients, 435 (51%) received ethambutol, 278 (32%) received cycloserine, and 145 (17%) received terizidone. Demographic and baseline clinical data were comparable. Successful treatment occurred in 56%, significantly more in patients receiving cycloserine (60%) and terizidone (62%) than in those receiving ethambutol (52% [ = 0.03]). Defaults rates were 30% in ethambutol patients versus 15% and 11% for cycloserine and terizidone patients, respectively. Terizidone was associated with fewer unfavorable outcomes (adjusted odds ratio [AOR], 0.4; = 0.008; 95% confidence interval [CI], 0.2 to 0.8). Patients receiving cycloserine were more likely to achieve culture conversion than those receiving ethambutol or terizidone (AOR, 2.2; = 0.02; 95% CI, 1.12 to 4.38). Failure to convert increased the odds of unfavorable outcomes (AOR, 23.7; < 0.001; 95% CI, 13 to 44). SADEs were reported in two patients receiving ethambutol, seven patients receiving cycloserine, and three receiving terizidone ( = 0.05). Ethambutol was associated with high culture conversion and default rates. Cycloserine achieved higher culture conversion rates than terizidone. Fewer patients on terizidone experienced SADEs, with lower default rates. The differences that we observed between cycloserine and terizidone require further elucidation.
Topics: Adult; Antitubercular Agents; Cycloserine; Drug-Related Side Effects and Adverse Reactions; Ethambutol; Humans; Isoxazoles; Oxazolidinones; Pharmaceutical Preparations; South Africa; Treatment Outcome; Tuberculosis, Multidrug-Resistant
PubMed: 33046491
DOI: 10.1128/AAC.00744-20 -
Industrial Psychiatry Journal Jan 2013We report a 21-year-old male who developed manic symptoms after addition of second line anti-tuberculosis treatment for his multidrug resistant tuberculosis. We...
We report a 21-year-old male who developed manic symptoms after addition of second line anti-tuberculosis treatment for his multidrug resistant tuberculosis. We identified cycloserine as offending drug; and discuss the management and possible neurobiological mechanisms as etiological explanation and implications of manic switch caused by cycloserine.
PubMed: 24459378
DOI: 10.4103/0972-6748.123636 -
The Cochrane Database of Systematic... 2002Evidence supports a role for the NMDA receptors in learning and memory. These can be modulated by the antibiotic D-cycloserine in such a way that the effect of the... (Review)
Review
BACKGROUND
Evidence supports a role for the NMDA receptors in learning and memory. These can be modulated by the antibiotic D-cycloserine in such a way that the effect of the excitatory transmitter substance glutamate is enhanced. A study on healthy subjects pretreated with scopolamine to mimic Alzheimer's disease showed a positive effect of D-cycloserine at low doses.
OBJECTIVES
To assess the efficacy and safety of D-cycloserine in patients with Alzheimer's disease.
SEARCH STRATEGY
The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 14 June 2001 using the terms: cycloserine, D-cycloserine, Alzheimer*.
SELECTION CRITERIA
Randomized, double-blinded and unconfounded trials comparing D-cycloserine with a control treatment.
DATA COLLECTION AND ANALYSIS
Two larger and two smaller randomized controlled trials were identified. The clinical global impression scale was used in all studies and was a primary outcome measure.
MAIN RESULTS
It was not possible to extract the results from the first phases of the two crossover studies and therefore the meta-analyses are based on the two parallel group 6-month studies. There was no indication of a positive effect favouring D-cycloserine for the numbers showing improvement at 6 months as assessed by the Clinical Global Impression for any dose. The number of withdrawals for any reason before end of treatment at 6 months was significantly in favour of placebo (fewer withdrawals) compared with D-cycloserine for dose levels of 30 mg/day (OR 2.94, 95% CI 1.52, 5.70) and 100 mg/day (OR 3.23, 95% CI 1.67, 6.25). There was no significant difference between treatment, (2, 10, 30, 100, or 200 mg/day) and placebo for the number of withdrawals due to adverse events by six months.
REVIEWER'S CONCLUSIONS
The lack of a positive effect of D-cycloserine on cognitive outcomes in controlled clinical trials with statistical power high enough to detect a clinically meaningful effect means that D-cycloserine has no place in the treatment of patients with Alzheimer's disease.
Topics: Alzheimer Disease; Anti-Infective Agents, Urinary; Antibiotics, Antitubercular; Cycloserine; Humans; Randomized Controlled Trials as Topic
PubMed: 12076471
DOI: 10.1002/14651858.CD003153