East Asian Arch Psychiatry 2024;34:141-6 | https://doi.org/10.12809/eaap2435

PERSPECTIVE

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Sonali Labhade, Dr DY Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, India
Ritesh Bhole, Dr DY Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, India; Dr DY Patil Dental College and Hospital, Dr DY Patil Vidyapeeth, Pimpri, Pune, India 
Smita Jain, Central University of Rajasthan, India

Address for correspondence: Dr Sonali Labhade, Dr DY Patil Institute of Pharmaceutical Sciences and Research, Pimpri, Pune, India. Email: sonali.labhade@dypvp.edu.in

Submitted: 2 August 2024; Accepted: 18 October 2024

Depression is characterised by enduring feelings of sadness, diminished interest or enjoyment, and impaired daily functioning. Despite availability of antidepressive medications, a proportion of patients still fail to attain adequate symptom relief or experience intolerable adverse effects.¹ These patients with treatment-resistant depression require alternative treatment options. Depression is a multifaceted psychiatric condition marked by disturbances in mood, cognition, and behaviour. However, conventional antidepressive medications primarily target monoaminergic neurotransmission only. S-adenosylmethionine (SAMe), a naturally occurring compound involved in various neurobiological processes of mood regulation, presents a promising treatment option.^2,3

We reviewed meta-analyses, randomised controlled trials, longitudinal studies, and combination therapy studies to elucidate SAMe’s mechanisms of action and its potential efficacy in managing depression. We also explored SAMe supplementation as an adjunctive therapy for individuals with treatment-resistant depression, its applications in other psychiatric disorders, and its effect on neurological diseases.

S-adenosylmethionine

SAMe is an endogenous compound involved in methylation reactions, neurotransmitter synthesis, and antioxidant defence mechanisms. SAMe serves as a methyl donor in transmethylation reactions, facilitating the synthesis of neurotransmitters such as serotonin, dopamine, and norepinephrine. Additionally, SAMe modulates neuroinflammatory pathways, enhances neuroplasticity, and regulates gene expression implicated in mood regulation. These mechanisms underlie the potential antidepressive effects of SAMe.⁴

Neurotransmitter metabolism

SAMe has been used for treating a variety of conditions, including depression, and is marketed as a mood and emotional wellbeing enhancer.⁵ The synthesis of SAMe from L-methionine occurs through a metabolic pathway called the one-carbon cycle. This partially depends on sufficient amounts of the vitamins folate and B12, and deficiency of these vitamins is associated with a higher risk of depression.⁶ For instance, 10% to 30% of individuals with depression have low folate concentrations and react less favourably to antidepressants. Conversion of vitamin B12 to methylcobalamin plays a crucial role in the synthesis of various neurotransmitters within the central nervous system; therefore, a lack of vitamin B12 might lead to an earlier onset of depression. Decreased levels of SAMe may be a common mediator, and therefore correcting deficiencies in folate and vitamin B12 can potentially alleviate symptoms of depression and improve the effectiveness of antidepressive medications, probably by increasing the concentration of SAMe.⁷ Individuals with depression have reduced quantities of SAMe in their cerebrospinal fluid; an increase in plasma SAMe concentrations is proportionally associated with an improvement in depressed symptoms.⁸ Individuals with depression and schizophrenia exhibit reduced activity of the enzyme methionine adenosyltransferase, which is involved in SAMe synthesis; however, the activity level is high in patients with manic episodes. Thus, SAMe may act as a mood-enhancing substance.

Modulation of neuroinflammation

Inflammation of the brain is associated with the onset of chronic conditions such as depression,⁹ schizophrenia,¹⁰ and Alzheimer disease (AD).¹¹ SAMe reduces cytokine and interleukin levels in lipopolysaccharide- stimulated monocytes and macrophages, acting as an anti-inflammatory agent.^12,13 SAMe’s pharmacological inhibition of inflammation mediators involves modification of the methylation capability and inhibition of the binding of trimethylated H3K4 to the tumour necrosis factor-α promoter, which increases methylthioadenosine and S- adenosylhomocysteine levels.¹⁴ Furthermore, administration of SAMe decreases phosphodiesterase 4B expression by enhancing the attachment of transcriptionally restrictive trimethylated H3K9 to its promoter region, consequently impeding tumour necrosis factor-α generation mediated by cyclic adenosine monophosphate.¹³ There is a decrease in the DNA methylation status of inflammatory genes in human macrophages following SAMe treatment.^15,16 Therefore, the anti-inflammatory efficacy of SAMe, via methylation regulation, may have effects on chronic inflammatory conditions.^17-19

Enhancement of neuroplasticity

Neuroplasticity is the capacity of the brain to adapt and reorganise itself in response to various stimuli; it is crucial for regulating mood and responding to antidepressive treatments. SAMe enhances neuroplasticity by promoting synaptic neurotransmission, neurogenesis, and dendritic spine density in key brain regions implicated in depression such as the prefrontal cortex and hippocampus. By facilitating structural and functional neuronal changes, SAMe fosters adaptive responses to stress and enhances resilience against depressive pathology.²⁰

Regulation of gene expression

DNA methylation is involved in the control of gene expression and the development and maintenance of cellular identity. DNA methylation can be disturbed by a variety of illnesses; gene expression can remain adaptable throughout time in response to variables that are either developmental or environmental.^21-23 Many DNA methylation markers have been implicated in the dynamics of gene regulation in the central nervous system (Table and Figure).^24-27

Clinical evidence

There is robust clinical evidence supporting the efficiency of SAMe supplementation in alleviating symptoms of depression, particularly in patients who have not responded optimally to standard antidepressive therapy.^8,28-31

SAMe versus placebo as adjunctive treatment

Oral administration of SAMe at dosages of 800 to 1600 mg/day resulted in significant reductions in depressive symptoms.⁸ In a 6-week trial comparing SAMe (800 mg/ twice daily) with placebo, the Hamilton Depression Rating Scale score response rate (36.1% vs 17.6%) and remission rate (25.8% vs 11.7%) were significantly higher among patients treated with adjunctive SAMe than with adjunctive placebo.¹⁹

SAMe versus imipramine or escitalopram as adjunctive treatment

SAMe’s efficacy as an adjunctive therapy for depression stems from its role as a methyl donor in vital biochemical reactions, including the synthesis and metabolism of key neurotransmitters such as serotonin, dopamine, and norepinephrine. SAMe promotes mood regulation and alleviates depressive symptoms. SAMe has been shown to reduce inflammation and oxidative stress, both of which are central to the pathophysiology of depression. SAMe can enhance the antidepressant effects of existing treatments, particularly in patients with major depressive disorder who have not responded adequately to selective serotonin reuptake inhibitors alone.

SAMe accelerates the onset of imipramine’s antidepressive effects in patients with depression, potentially due to their combined action on serotonin 1A (5-HT1A) receptors.²⁵ Compared with saline, imipramine alone upregulated the 5-HT1A receptor levels in the frontal cortex but failed to induce an antidepressive effect, whereas SAMe alone or in combination with imipramine did not affect 5-HT1A receptor levels in the frontal cortex but showed antidepressive effects. Long-term treatments with SAMe, imipramine, or their combination resulted in both antidepressive effects and upregulation of 5-HT1A receptor levels in the hippocampus. Interestingly, SAMe inhibited the upregulation of 5-HT1A receptors in the frontal cortex caused by imipramine. This interaction may contribute to the antidepressive effect of imipramine.

SAMe, escitalopram, and placebo resulted in significant improvement in depression symptoms, as measured by the Hamilton Depression Rating Scale, from baseline to week 12.²⁶ The effect size for SAMe versus placebo was moderate to large (d=0.74). SAMe was superior to placebo as early as week 1. SAMe outperformed escitalopram during weeks 2, 4, and 6. Compared with escitalopram and placebo, SAMe achieved the highest response rate (45% vs 31% vs 26%) and remission rate (34% vs 23% vs 6%).

SAMe for psychiatric disorders

Aggression in people with schizophrenia is associated with a particular genetic variation in the catechol- O-methyltransferase (COMT) gene, which leads to downregulation of an enzyme that aids in neurotransmission.³² SAMe mitigated aggression in a subset of patients with schizophrenia by increasing COMT enzyme activity. Patients with chronic schizophrenia and genotype associated with reduced COMT activity were randomly assigned to receive SAMe or placebo; the SAMe group exhibited a significant reduction in aggression, as measured by the Overt Aggressiveness Scale.

The 22q11.2 deletion syndrome, involving deletion of one copy of the COMT gene, is a genetic disorder that frequently associated with mental health conditions such as psychosis, depression, and attention deficit hyperactivity disorder.³³ SAMe may enhance COMT enzymatic activity, potentially alleviating mental symptoms in these patients. In a study assessing the feasibility and safety of SAMe in 12 patients with 22q11.2 deletion syndrome, SAMe treatment up to 1600 mg/day for 6 weeks appeared to be safe, well tolerated, with no serious adverse effects.³⁴

SAMe for chronic inflammation in Alzheimer
disease

SAMe plays a crucial role in metabolic pathways that are essential for maintaining brain homeostasis. SAMe acts as a methyl donor, which affects gene expression via DNA methylation. This process leads to the production of several substances including neurotransmitters and phosphatases.³⁵ SAMe also plays a crucial role in transsulphuration, a process that generates glutathione, the brain’s primary antioxidant. Additionally, SAMe is involved in the production of neuroregulatory polyamines, which possess anti-inflammatory characteristics and are responsible for regulating cell differentiation and proliferation. The proper functioning of these processes and subsequently of neurons relies on a sufficient supply of SAMe.

Patients with AD have significantly decreased quantities of SAMe in both their cerebrospinal fluid and post-mortem brain tissue.³⁶ Possible causes include a lack of B12 or folate because these nutrients are necessary in producing methionine.³⁷ Another potential cause could be the excessive use of SAMe in the synthesis of polyamines, which may be a result of a persistent inflammatory response to tau pathology. High levels of homocysteine, which occur secondary to B12 or folate deficiency, might also hinder the methylation activity of SAMe by providing negative feedback to the enzymes involved in the methionine cycle.³⁸ The SAMe deficiency seen in the AD brain can be caused by hyperhomocysteinaemia, malnutrition, increased SAMe consumption during polyamine production in the presence of persistent neuronal inflammation, and other unidentified processes. Deficiency of SAMe is responsible for pathogenic processes that are hallmarks of AD; for example, without methylation, protein phosphatase 2A, the primary phosphatase in the brain, becomes ineffective, leading to uncontrolled tau hyperphosphorylation. The expression of genes associated with AD is a consequence of the loss of methylation in their promotors. The decrease in brain acetylcholine levels is caused by a deficiency in SAMe-mediated methylation of N-methyl nicotinamide. This deficiency often hinders the normal outflow of acetylcholine from the brain. The depletion of brain glutathione levels caused by the loss of SAMe-mediated transsulphuration impairs cerebral antioxidant action and perpetuates neuroinflammation. Irrespective of the reason, a shortage of SAMe affects several important processes that result in the pathogenesis of AD. Deficiency in SAMe can increase the expression of genes that promote the development and progression of AD, leading to elevated production of amyloid beta. It also impairs the production and retention of acetylcholine in the brain, disrupts the function of phosphatase, causes an accumulation of hyperphosphorylated tau, and obstructs the ability of glutathione to neutralise reactive oxygen species, thereby promoting a state of neuroinflammation. SAMe exhibits potential neuroprotective effects in mitigating cognitive impairment associated with brain ageing, primarily by inhibiting oxidative stress, neuroinflammation, and alpha 7 nicotinic acetylcholine receptors signalling pathways.³⁹ Administration of SAMe in individuals with AD led to improvements in cognitive performance and severity of dementia symptoms, and the treatment was well-tolerated.

Limitations

The studies included in this review are susceptible to biases or variations in methodologies. Consequently, the generalisability of our findings may be affected by the heterogeneity of study populations and methodologies. Although the mechanisms of SAMe in terms of neurotransmitter metabolism, neuroinflammation, neuroplasticity, and gene expression regulation have been delineated to a degree, the precise molecular pathways and interactions remain incompletely understood. Further elucidation of these mechanisms is essential to optimise interventions and customise strategies to individual patients. Although SAMe supplementation is effective for depression management, comprehensive evaluation of its adverse effects, optimal dosages, treatment durations, drug interactions, and long-term safety profile is warranted to inform clinical practice. Future studies should assess the safety and tolerability of SAMe, particularly in pregnant women, children, and older adults.

Conclusion

SAMe supplementation can alleviate depression symptoms in patients with suboptimal response to standard antidepressive therapy. Current evidence suggests that SAMe, through modulating methylation processes and neurotransmitter function, may provide a complementary treatment. SAMe is a promising candidate for enhancing mental and neurological health through both standalone and adjunctive therapies.

Contributors

All authors designed the study, acquired the data, analysed the data, drafted the manuscript, and critically revised the manuscript for important intellectual content. All authors had full access to the data, contributed to the study, approved the final version for publication, and take responsibility for its accuracy and integrity.

Conflicts of interest

All authors have disclosed no conflicts of interest.

Funding / support

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Data availability

All data generated or analysed during the present study are available from the corresponding author on reasonable request.

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