Feasibility, Safety, and Efficacy of the Combination of D-Serine and Computerized Cognitive Retraining in Schizophrenia: An International Collaborative Pilot Study

D’Souza, Deepak Cyril; Radhakrishnan, Rajiv; Perry, Edward; Bhakta, Savita; Singh, Namrata; Yadav, Richa; Abi‐Saab, Danielle; Pittman, Brian; Chaturvedi, Santosh K.; Sharma, Mohit; Bell, Morris D.; Andrade, Chittaranjan

doi:10.1038/npp.2012.208

Cited by 64 publications

(53 citation statements)

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“…D-serine, DCS, and related compounds are of particular interest because of their widespread use and a favorable safety profile, and also the moderate modulatory effects of such compounds that avoids more severe side effects of some NMDAR modulators (Heresco-Levy et al, 2013;Millan, 2005;Tsai and Lin, 2010). We note that nephrotoxicity is a potential concern with long-term, high-dose treatment of D-serine (Krug et al, 2007), but several longer-term D-serine studies have been performed in humans without adverse effects noted (D'Ascenzo et al, 2014;D'Souza et al, 2013;Heresco-Levy et al, 2013;Kantrowitz et al, 2010;Tsai and Lin, 2010). In addition, D-serine and DCS can enhance NMDAR activity and increase memory (Heresco-Levy et al, 2013;Martineau et al, 2014;Sani et al, 2012;Tsai and Lin, 2010).…”

Section: Discussionmentioning

confidence: 98%

“…There has long been interest in using NMDAR modulators to address a number of human conditions, for example, to suppress the enhanced glutamatergic function associated with protracted alcohol consumption (Gass and Olive, 2008;Krystal et al, 2003Krystal et al, , 2011Spanagel, 2009), and to enhance memory as well as overcome decreased NMDAR function that may contribute to schizophrenia, Parkinson's disease, and cocaine addiction (D'Ascenzo et al, 2014;Heresco-Levy et al, 2013;Martineau et al, 2014;Sani et al, 2012;Tsai and Lin, 2010). Modulators of the NMDAR glycine site, such as D-serine and D-cycloserine (DCS), are of particular interest because of their use in many patient populations with few side effects or safety issues noted (D'Ascenzo et al, 2014;D'Souza et al, 2013;Heresco-Levy et al, 2013;Kantrowitz et al, 2010;Tsai and Lin, 2010; but see Krug et al, 2007), and because the moderate NMDAR inhibition these reagents afford is considered more favorable than stronger NMDAR inhibitors that can have significant adverse effects (cf, Heresco-Levy et al, 2013;Millan, 2005).…”

Section: Introductionmentioning

confidence: 99%

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D-Serine and D-Cycloserine Reduce Compulsive Alcohol Intake in Rats

Seif

Simms

Lei

et al. 2015

Neuropsychopharmacol

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There is considerable interest in NMDAR modulators to enhance memory and treat neuropsychiatric disorders such as addiction, depression, and schizophrenia. D-serine and D-cycloserine, the NMDAR activators at the glycine site, are of particular interest because they have been used in humans without serious adverse effects. Interestingly, D-serine also inhibits some NMDARs active at hyperpolarized potentials (HA-NMDARs), and we previously found that HA-NMDARs within the nucleus accumbens core (NAcore) are critical for promoting compulsion-like alcohol drinking, where rats consume alcohol despite pairing with an aversive stimulus such as quinine, a paradigm considered to model compulsive aspects of human alcohol use disorders (AUDs). Here, we examined the impact of D-serine and D-cycloserine on this aversion-resistant alcohol intake (that persists despite adulteration with quinine) and consumption of quinine-free alcohol. Systemic D-serine reduced aversion-resistant alcohol drinking, without altering consumption of quinine-free alcohol or saccharin with or without quinine. Importantly, D-serine within the NAcore but not the dorsolateral striatum also selectively reduced aversion-resistant alcohol drinking. In addition, D-serine inhibited EPSCs evoked at -70 mV in vitro by optogenetic stimulation of mPFC-NAcore terminals in alcohol-drinking rats, similar to reported effects of the NMDAR blocker AP5. Further, D-serine preexposure occluded AP5 inhibition of mPFC-evoked EPSCs, suggesting that D-serine reduced EPSCs by inhibiting HA-NMDARs. Systemic D-cycloserine also selectively reduced intake of quinine-adulterated alcohol, and D-cycloserine inhibited NAcore HA-NMDARs in vitro. Our results indicate that HA-NMDAR modulators can reduce aversion-resistant alcohol drinking, and support testing of D-serine and D-cycloserine as immediately accessible, FDA-approved drugs to treat AUDs.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

D-Serine and D-Cycloserine Reduce Compulsive Alcohol Intake in Rats

Seif

Simms

Lei

et al. 2015

Neuropsychopharmacol

View full text Add to dashboard Cite

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“…The financial rewards of innovation may seem greater, reasonably motivating new treatments for these disorders in lieu of less lucrative mental health and substance use disorders. It also may be that potential medications such as pro-cognitive drugs for schizophrenia might be more effective if linked with cognitive retraining, with clinical trials considering dual avenues of treatment (55). Coordinated treatment that reaches beyond pharmacotherapy may be more essential with psychiatric disorders, further limiting investment in psychotropic development.…”

Section: Discussionmentioning

confidence: 99%

The Diminished Pipeline for Medications to Treat Mental Health and Substance Use Disorders

O’Brien¹,

Thomas²,

Hodgkin³

et al. 2014

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Objective Psychotropic drug development is perceived to be lagging behind other pharmaceutical development even though there is a need for more effective psychotropic medications. This article examines the state of the current psychotropic drug pipeline and potential barriers to psychotropic drug development. Methods We scanned the recent academic and “grey” literature to evaluate the current state of psychotropic drug development and to identify experts in the fields of psychiatry and substance use disorder treatment and psychotropic drug development. Based on that preliminary research, we interviewed six identified experts and then analyzed drugs in Phase III development for major psychiatric disorders. Results Our interviews and review of clinical trials for drugs in Phase III of development confirm that the psychotropic pipeline is slim and that the majority of drugs presently in Phase III trials are not very innovative. Among the barriers to development are incentives that encourage firms to focus on incremental innovation rather than taking risks on radically new approaches. Other barriers include human brain complexity, failure of animal trials to translate well into human trials, and a drug approval threshold that is perceived to be so high as to discourage development. Conclusions Drivers of innovation in psychotropic drug development largely parallel those for other drugs, yet crucial distinctions have led to slowing psychotropic development after a period of innovation and growth. Various factors have acted to dry up the pipeline for psychotropic drugs, with expert opinion suggesting that in the near term, this trend is likely to continue.

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“…; D'Souza et al . ). The facilitation of cognitive abilities is promising for the enhancement of extinction learning by d ‐serine in patients with substance abuse.…”

Section: Enhancing Extinction Through Pharmacological Methods—clinicamentioning

confidence: 99%

Recent developments in the behavioural and pharmacological enhancement of extinction of drug seeking

Chesworth

Corbit

2015

Addiction Biology

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One of the principal barriers to overcoming addiction is the propensity to relapse, even after months or years of abstinence. Relapse can be precipitated by cues and contexts associated with drug use; thus, decreasing the conditioned properties of these cues and contexts may assist in preventing relapse. The predictive power of drug cues and contexts can be reduced by repeatedly presenting them in the absence of the drug reinforcer, a process known as extinction. The potential of extinction to limit relapse has generated considerable interest and research over the past few decades. While pre-clinical animal models suggest extinction learning assists relapse prevention, treatment efficacy is often lacking when extinction learning principles are translated into clinical trials. Conklin and Tiffany (Addiction, 2002) suggest the lack of efficacy in clinical practice may be due to limited translation of procedures demonstrated through animal research and propose several methodological improvements to enhance extinction learning for drug addiction. This review will examine recent advances in the behavioural and pharmacological manipulation of extinction learning, based on research from pre-clinical models. In addition, the translation of pre-clinical findings-both those suggested by Conklin and Tiffany () and novel demonstrations from the past 13 years-into clinical trials and the efficacy of these methods in reducing craving and relapse, where available, will be discussed. Finally, we highlight areas where promising pre-clinical models have not yet been integrated into current clinical practice but, if applied, could improve upon existing behavioural and pharmacological methods.

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Feasibility, Safety, and Efficacy of the Combination of D-Serine and Computerized Cognitive Retraining in Schizophrenia: An International Collaborative Pilot Study

Cited by 64 publications

References 48 publications

D-Serine and D-Cycloserine Reduce Compulsive Alcohol Intake in Rats

D-Serine and D-Cycloserine Reduce Compulsive Alcohol Intake in Rats

The Diminished Pipeline for Medications to Treat Mental Health and Substance Use Disorders

Recent developments in the behavioural and pharmacological enhancement of extinction of drug seeking

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