Psychiatric Annals

Review Article 

D-Cycloserine: A Novel Antidepressant to Be Explored?

Navjot Brainch, MD; Sanya Virani, MD, MPH; Lama Bazzi, MD

Abstract

The shortcomings of existing antidepressants used in patients with treatment-resistant depression have evoked much interest in exploring novel yet cost-effective drugs that target N-methyl D-aspartate receptors. In addition to ketamine, evidence for the effectiveness of the antituberculosis drug D-cycloserine (DCS) in this realm has also been steadily accumulating. Systematic searches of the PubMed, Cochrane, and MEDLINE Plus databases were conducted to identify studies on the antidepressant effects of DCS. Results from one case series, four double-blinded trials, and two open-label studies comprising a total of 134 participants who had received DCS are summarized. These studies reported that DCS was safe and well tolerated, and four of them showed a reduction in depressive symptoms without psychomimetic and dissociative effects. We present the limited but convincing evidence to suggest the promising antidepressant properties of DCS when administered independently at high dose or as an adjuvant in controlled settings. [Psychiatr Ann. 2018;48(4):193–198.]

Abstract

The shortcomings of existing antidepressants used in patients with treatment-resistant depression have evoked much interest in exploring novel yet cost-effective drugs that target N-methyl D-aspartate receptors. In addition to ketamine, evidence for the effectiveness of the antituberculosis drug D-cycloserine (DCS) in this realm has also been steadily accumulating. Systematic searches of the PubMed, Cochrane, and MEDLINE Plus databases were conducted to identify studies on the antidepressant effects of DCS. Results from one case series, four double-blinded trials, and two open-label studies comprising a total of 134 participants who had received DCS are summarized. These studies reported that DCS was safe and well tolerated, and four of them showed a reduction in depressive symptoms without psychomimetic and dissociative effects. We present the limited but convincing evidence to suggest the promising antidepressant properties of DCS when administered independently at high dose or as an adjuvant in controlled settings. [Psychiatr Ann. 2018;48(4):193–198.]

The lack of efficacy of existing antidepressants used in patients with treatment-resistant depression has led to interest in exploring alternate drugs that target N-methyl D-aspartate (NMDA) receptors. In addition to trials on ketamine, studies testing the effectiveness of the antituberculosis drug D-cycloserine (DCS) for depression have also been done, and the evidence of its efficacy is steadily accumulating.1–7 DCS acts as a partial agonist at the NMDA receptor-associated glycine site at low doses and as an antagonist at higher doses. In this review, we present the limited but convincing evidence that suggests the promising antidepressant properties of DCS when administered independently at high doses or as an adjuvant, albeit in controlled research settings.

Review of D-Cycloserine: Properties and Mechanism of Action

DCS is used in the treatment of active drug-resistant tuberculosis and some urinary tract infections when conventional antibiotics fail. Its bacteriostatic properties include competing with the amino acid D-alanine for incorporation into the bacterial cell wall, thereby inhibiting bacterial cell wall synthesis. Oral doses recommended by the American Thoracic Society (ATS) for the treatment of tuberculosis range between 250 and 500 mg every 12 hours for 14 days, or 10 to 15 mg/kg per day in two divided doses, for a maximum of 1,000 mg/day.8

DCS in Depression

DCS acts as a partial agonist at the strychnine-insensitive glycine modulatory site of the GluN1 subunit of the NMDA receptor. It binds at the GluN1 receptor with higher affinity than glycine, so it opens the ion channel, leading to an influx of calcium. This activates postsynaptic neuronal nitric oxide synthase to increase the production of nitric oxide, which in turn activates guanyl cyclase and increases the release of cyclic guanosine monophosphate (cGMP).

In the absence of glycine, DCS increases NMDA-mediated synaptic responses, leading to increased stimulation of the receptor by glutamate; however, this response is inhibited in the presence of glycine. This dual action is mediated through the cGMP/nitric oxide (NO) system of the glutamate receptor complex.9 DCS brings about an increase and decrease in c-GMP at low and high doses, respectively.9 Controversies exist in the literature about the dose at which DCS acts as an antagonist. Millan10 suggested DCS >100 mg/day exhibited antagonist properties, whereas van Berckel et al.11,12 suggested that a dose of >500 mg/day may be required to generate a neuroendocrine response, which is caused by NMDA receptor antagonist activity.

DCS in Other Psychiatric Conditions

The exact mechanism of action of DCS in schizophrenia is unclear, although the glutaminergic system is linked to some symptoms. A study conducted by Andreasen in 198213 showed a dose-dependent improvement in negative symptoms (affective flattening, alogia, avolition, anhedonia, and attention impairment) in patients with schizophrenia. Studies by Goff et al.14 and Heresco-Levy et al.15 showed best results with daily doses of 50 mg of DCS, but later reports by Goff et al.16,17 and van Berckel et al.18 demonstrated that the combination of DCS with clozapine or olanzapine led to worsening of negative symptoms. More recent studies have shown that DCS had no or only marginal effect on negative symptoms.19–21 Results of two meta-analyses found other glutaminergic drugs to be more efficient than DCS for the treatment of schizophrenia symptoms, primarily due to the latter's narrow therapeutic range due to its partial agonistic mechanism.22,23

The role of DCS in anxiety and panic disorders (mainly obsessive-compulsive disorder, eating disorders, and phobias) and neurological disorders (dementia, Alzheimer's disease, and spino-cerebellar degeneration) has evoked much interest. Through its action on the NMDA receptor, DCS affects long-term potentiation24 and increases cortical neuroplasticity (which is hypothesized to be the reason it improves cognition (in dementia), facilitates new learning in cognitive-behavioral therpay/exposure therapy, and extinction learning in addiction.25

Methods

Systematic searches of the PubMed, Cochrane, and MEDLINE Plus databases were conducted using a combination of keywords such as “D-cycloserine,” “depression,” and “antidepressant.” The search was narrowed to include only those articles to date that specifically addressed the treatment of depression with DCS, even as an adjunct to other medications or modes of treatment. Figure 1 shows the step-by-step process of article selection.

Flowchart for selection of review articles.

Figure 1.

Flowchart for selection of review articles.

Results

Results from four double-blinded trials, two open-label studies, and one case series comprising a total of 134 participants who received DCS are summarized in Table 1.

Salient Features of Studies ReviewedSalient Features of Studies Reviewed

Table 1.

Salient Features of Studies Reviewed

Conclusion

This review attempted to tabulate details of design, patient population, methods, and results of selected studies of DCS and make recommendations for exploring further research avenues.

All of the studies included in this review reported that DCS was safe and well-tolerated, supporting findings from the existing literature.1 Five of these studies even showed that DCS resulted in marked reduction of depressive symptoms without causing significant psychomimetic and dissociative effects, which are sometimes seen with the administration of ketamine. One important conclusion supported by Heresco-Levy et al.2 was the effectiveness of DCS as an antidepressant only at high doses. Kushner et al.3 and Wilhelm et al.,4 in their study of patients with OCD, concluded there was significant improvement in depression independent of improvement in OCD. The two studies that did not show positive results are likely to have not succeeded because of suboptimal dosing.5,6 Additionally, Kantrowitz et al.1 reported that there is a fairly strong positive correlation between acute and late favorable responses to DCS, suggesting that initial response predicts improvement after several weeks, consistent with findings by Heresco-Levy et al.2 reported over a similar span of time. However, studies have also indicated that the pharmacological interactions between DCS and ongoing antidepressant medications cannot be overlooked.

Although mostly conducted on smaller patient populations, these studies have provided some valuable information about the properties of this drug that has existed for decades and is now being studied for alternate indications. All of the studies in this review show that there are gaps in the literature, and research on this topic and indicate the necessity of conducting larger trials with bigger sample sizes to determine optimal dosing regimens.

Another issue that remains largely unexplored is the potential for DCS to be used as an independent antidepressant rather than as an adjuvant, especially in combination with ketamine or transcranial direct current stimulation. Ketamine infusions are known to bring about rapid resolution of depressive symptoms but the positive effects do not last long in a large percentage of recipients.26,27 DCS has the advantage of once-daily oral dosing and no requirement for strict monitoring when compared with ketamine. In sum, DCS is a cost-effective novel therapy but there is a need for extensive research to potentially establish its place as an innovative antidepressant in managed-care settings.

References

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Salient Features of Studies Reviewed

Reference, Year Study Design Study Population Intervention(s) Result(s) Limitation(s)
Crane,7 1959 Case series Group A: 31 patients (16 men and 15 women, age 19–67 years) with various forms of tuberculosis Group B: 19 patients (11 men and 8 women, age 33–63 years) with slowly progressive tuberculosis and depression Daily oral dose of cycloserine (500–2,000 mg) for 4–30 months Daily oral dose of cycloserine (500–750 mg) for 1 year Results observed in 11, 8, and 8 patients at 2 weeks, 1 month, and 1–6 months, respectively <list-item>

Reduction in or complete reversal of symptoms of anorexia in 23, asthenia in 25, and insomnia in 15 patients

</list-item><list-item>

Reduction in feelings of apathy and inadequacy, phobias, and somatic symptoms

</list-item>
Treatment discontinuation in some patients in both groups due to early toxicity leading to bias in regards to toxic reactions
Heresco-Levy et al.,5 2006 Double-blinded, placebo-controlled crossover trial 22 patients (12 men and 10 women, age 56.9 ± 12.4 years) with treatment-resistant depression Participants that received at least 4 weeks of treatment with adequately dosed antidepressant drug, scoring ≥18 on the HAMD, and showing at most mild improvement in depressive symptoms from treatment onset were included Randomly assigned to receive daily oral dose of 250 mg of DCS or placebo for 6 weeks as adjuvant to the current antidepressant medication regimen Then underwent 2-week treatment washout period, followed by 6 weeks of crossover treatment Improvement in HAMD, Hamilton Rating Scale for Anxiety and Zung Self-Rating Depression Scale scores: <list-item>

Mean ± SD (percentage improvement): 2.2 ± 7.63 (11.8%), 4.37 ± 6.77 (21.1%), and 6.42 ± 9.06 (11.4%)

</list-item><list-item>

This outcome did not differ significantly from the effects during the placebo treatment phase

</list-item>
Antidepressant regimen was continued Lengths of treatment periods prior to trial were variable and dose ranges nonuniform Only 16 patients completed treatment phase and 6 weeks of active treatment period, which was too short to evidence full DCS treatment potential
Kushner et al.,3 2007 Double-blinded RCT with treatment and placebo groups 32 patients with DSM-IV primary diagnosis of OCD and ≥18 on Y-BOCS Group A: DCS group (N = 15) Group B: Placebo group (N = 17) Patients with primary diagnosis of hoarding or ordering rituals, pregnant, lactating, and those who met criteria for current major depression or substance use disorder were excluded 10 weekly doses of 125 mg oral DCS or placebo at least 2 hours before exposure/ritual prevention therapy session No differences in posttreatment OCD symptoms but statistically significant improvements in BDI scores from baseline (P = .023) Baseline mean (SD) BDI scores in treatment and placebo changed from 13.4 (11.4) and 10.6 (10.3) to 3.3 (5.6) and 9.5 (10.9), respectively, posttreatment (P = .023). Comorbidities other than mood disorder and substance use disorder were not assessed and so could not be compared between groups Extra-study psychiatric regimen was continued if doses were stable for 2 months prior to start of study
Wilhelm et al.,4 2008 Double-blinded RCT with treatment and placebo groups 23 patients with DSM-IV primary diagnosis of OCD Group A: DCS group (N =10) (age 40 ± 13.4 years) Group B: Placebo group (N = 13) (age 38.2 ± 13 years) 100 mg of DCS or placebo was given 1 hour before each of 10 therapy sessions (60 minutes) 2 times per week No statistically significant differences in posttreatment OCD symptoms but statistically significant improvements in BDI scores from baseline (P = .04). Baseline mean (SD) BDI scores in treatment and placebo changed from 10.9 (8.3) and 15.5 (12.7) to 8.7 (9.1) and 1.9 (3.3), respectively, posttreatment (P = .04) No limitations reported; however, when compared with the study by Kushner et al.21 the dosing and timing of administration were different
Heresco-Levy et al.,2 2013 Double-blinded RCT with parallel treatment and placebo groups 26 patients (10 men and 16 women, age 53.0 ± 10.2 years) with treatment-resistant recurrent MDD (HAMD Score ≥20). Group A: DCS group (N = 13) Group B: Placebo group (N = 13) Group A: Oral DCS gradually titrated to a maximum daily dose of 1,000 mg for a total of 6 weeks 250 mg/day for 3 days; 500 mg/day for 18 days; 750 mg/day for 1 week; and 1,000 mg/day for the past 2 weeks Significant reduction in depressive symptoms, HAMD (P = 0.005) and self-reported BDI scores (P = 0.046) Of the 13 patients treated with DCS, 54% had a >50% HAMD score reduction vs 15% of the 13 patients randomized to placebo (P = 0.039) Small sample size Limited number of assessment scales used DCS used as an adjuvant; pharmacological interactions between DCS and the ongoing antidepressant medications could not be excluded
Chan et al.,6 2013 Open-label pilot study 5 patients (2 men and 3 women, age 36–60 years) Patients diagnosed with a major depressive episode per DSM-IV criteria did not achieve remission or relapsed within 1 month of completing Index study (MADRS score of <10) were included. Group A: 2 patients (2 women age 37 and 60 years). Group B: 3 patients (2 men and 1 woman age 59, 41, and 60 years, respectively). Double-blinded sham/active tDCS for sessions 1–15; then open- label for sessions 16-30 Open-label tDCS + cycloserine for 20 sessions; 100 mg of oral DCS 2 hours before tDCS sessions 3 patients did not respond to tDCS and 2 patients that responded to tDCS failed to maintain that effect at week 1, showing no enhancement of tDCS by DCS, which was attributed to either suboptimal dosing, small sample size or poorly understood interactions between DCS and serotonergic agents that these patients were taking Small sample size Participants were blinded to whether they were receiving active or sham tDCS for the first 15 sessions; however, cycloserine/tDCS course was given on an open-label basis
Kantrowitz et al.,1 2015 Open-label pilot study 8 patients (3 men and 5 women, age 36 ± 16 years) Patients with current diagnosis of bipolar disorder 1 or 2 (DSM-IV-TR), having a MADRS score >20, with no current or chronic psychosis or substance dependence and resistant to antidepressant regimen for 3 to 4 months were included IV ketamine hydrochloride (0.5 mg/kg over 1 hour) 8 weeks of oral DCS (250 mg/day titrated to 1,000 mg/day over 3 weeks) plus pyridoxine; continuing mood stabilizers (fluoxetine/olanzapine (N = 2), lurasidone (N = 4), or quetiapine (N = 2) Of the 7 patients that completed the study, 4 met remission criteria at 8 weeks (HAMD score <7) On mixed model analysis, a significant overall response over time was seen (P < .001) Small sample size Antidepressant/mood stabilizer regimen was continued Nonplacebo, controlled open-label design
Authors

Navjot Brainch, MD, is a third-year Psychiatry Resident. Sanya Virani, MD, MPH, is a second-year Psychiatry Resident. Lama Bazzi, MD, is the Psychiatry Inpatient Unit Director, and an Attending Physician. All authors are affiliated with the Department of Psychiatry, Maimonides Medical Center.

Address correspondence to Navjot Brainch, MD, Department of Psychiatry, Maimonides Medical Center, 920 48th Street, Brooklyn, NY 11219; email: navjot.brainch@gmail.com.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/00485713-20180308-01

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