Page 87 - ITPS-8-1

INNOSC Theranostics and
Pharmacological Sciences Brain glutamate level after treatment with NAC

1. Introduction system. This system has recently gained interest as a
possible treatment target for OCD. 10,30,31 Glutamatergic
According to the American Psychiatric Association (2013), drugs can function as ion-channel modulators, coagonists,
obsessive–compulsive disorder (OCD) is a chronic and reuptake inhibitors, and receptor antagonists. Changes in
debilitating mental illness, characterized by repetitive glutamate levels could influence the onset and persistence
behaviors or mental activities (compulsions) and frequent of OCD symptoms. Glutamate is the primary excitatory
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and intrusive thoughts, images, or urges (obsessions). The neurotransmitter of the cortico-striatal-thalamo-cortical
1
lifetime prevalence of OCD in the United States is 1 – 3%. (CSTC) circuit and is essential for the proper development
2,3
According to Algin et al. (2016), 70% of adult patients in of the CSTC circuitry, neuronal transmission, plasticity,
Bangladesh have moderate-to-severe OCD. OCD and and general brain function. Increasing evidence
4
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other anxiety disorders are the sixth most common causes correlates the pathophysiology of OCD to disruptions in
5
of non-fatal health loss worldwide. OCD is predominantly glutamate neurotransmission, in addition to the serotonin
related to disability and an increased risk of early death. transporter system. 34-38 Reportedly, the cerebrospinal fluid
6,7
The American Psychiatric Association included OCD as a of patients with OCD has a substantially higher glutamate
separate category in the Diagnostic and Statistical Manual level than that of healthy controls. 37,39 High glutamate levels
of Mental Disorders (DSM)version 5, replacing its previous are associated with oxidative stress and excitotoxicity and
8
classification as an anxiety disorder. Notably, patients with can be related to the intensity of OCD symptoms. 40,41
OCD also experience impairments in cognitive skills, such
as attention, memory, decision-making, and inhibitory Due to the importance of glutamate, new treatment
control. 9 approaches have been developed. The glutamatergic
system is targeted and modulated by N-acetylcysteine
Although several mechanisms, including oxidative
stress, infection, inflammation, autoimmune processes, (NAC), a derivative of the amino acid cysteine. NAC
contributes to cysteine, which is essential for glutathione
and disorganized neurotransmission, have been proposed (GSH) production. Although cysteine is not used in this
as underlying causes, the specific etiology of OCD remains process, it is transported across the blood–brain barrier
unknown. 10,11 An abnormality in the serotonin pathway is by sodium-dependent mechanisms. After entering the
considerably the primary cause of its development, due central nervous system, it undergoes oxidation to produce
to its selective sensitivity to serotonergic medications. cysteine. Through a cystine–glutamate antiporter,
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The involvement of glutamate, dopamine, and other
neurochemicals has been reported. Serotonergic astrocytes exchange cysteine for glutamate, which is
12
antidepressants (selective serotonin reuptake inhibitors released into the extracellular space. This activation of
[SSRIs]) are recommended as first-line therapy by inhibitory metabotropic glutamate receptors mGLuR2/3
on glutamatergic nerve terminals reduces the amount of
most clinical practice guidelines. 13,14 However, first-line synaptically released glutamate. 43,44
treatments and other augmentation measures do not
sufficiently treat 40 – 60%of patients with OCD. 15-18 In Furthermore, GSH enhances the NMDA receptor
addition, psychological treatments take time and are not response to glutamate in the brain. Consequently, altered
affordable for some patients. Moreover, full functional neuronal GSH levels may directly affect glutamatergic
recovery is relatively rarely achieved, and high doses of function, in addition to changing the amount of accessible
SSRIs prescribed for patients with OCD involve side effects, glutamate. NAC may also have biological effects on
45
such as sleepiness, insomnia, and sexual dysfunction. 19-21 the brain, which are potentially related to OCD, such
These factors often demand the use of additional adjunctive as reducing the production of inflammatory cytokines
treatments. 22-25 Numerous strategies have been attempted and modifying dopamine release. These characteristics
to improve treatment response, from adding cognitive would increase growth factors, such as brain-derived
behavioral therapy to elevating serotonergic action by neurotrophic factor, and regulation of neuronal cell death
26
increasing the dosage, combining SSRIs, or using the through the expression of B-cell lymphoma 2, in addition
intravenous route. 27,28 In addition, other medications have to oxidative stress reduction and glutamatergic balance
been attempted, including neuroleptics, anticonvulsants, restoration. 42,44
opioids, and neurosurgical techniques. 29 To the best of our knowledge, only seven randomized
Numerous glutamate-modulating medications, such controlled trials have examined the potential effectiveness
as lamotrigine, riluzole, and memantine, have been of NAC as an augmentation treatment for OCD, four
evaluated as monotherapy or augmentation therapies for of which revealed that taking 2,000 – 3,000 mg/day
OCD treatment. Reportedly, the pathophysiology of significantly decreased the Yale–Brown Obsessive–
30
OCD may be influenced by an impaired glutamatergic Compulsive Scale (Y-BOCS) scores. 46-52 In a 12-week

Volume 8 Issue 1 (2025) 81 doi: 10.36922/itps.4887