Chai-Hu-Jia-Long-Gu-Mu-Li-Tang for Depression Treatment: Untapped Potential of Traditional Chinese Herbs?

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Researchers have uncovered new evidence that a traditional Chinese herbal medicine may be a safe, effective option for treating depression.

The formula, known as Chaihu-jia-Longgu-Muli-tang (CLM) also phrased “Chai Hu Jia Long Gu Mu Li Tang,” outperformed standard antidepressants in clinical trials and appears to work via multiple mechanisms in the brain.

Key findings:

  • In clinical trials, CLM alone or combined with antidepressants like SSRIs led to significantly higher recovery rates and fewer side effects than antidepressants alone.
  • CLM alleviated not just depression but also common related symptoms like anxiety and insomnia more than antidepressants alone.
  • The formula reduced inflammatory markers like IL-6 and TNF-alpha, which are often elevated in depression.
  • Network analysis suggests CLM influences synaptic plasticity, inflammation, and neuronal survival via targets like PIK3R1, MAPK3, and AKT1.

Source: Front Pharmacol. 2023

An Urgent Need for Better Depression Treatments

Depression is a serious global health crisis affecting over 300 million people worldwide.

Unfortunately, currently available treatments like SSRIs leave much to be desired.

At least 30% of patients fail to respond, and many more struggle with side effects or relapse after initial improvement.

There is an urgent need for safer, more effective options.

Some clinicians have begun looking to traditional medicines like Chinese herbal formulas as potential alternatives.

These combinations of herbs have been used for centuries to treat diseases but have not been thoroughly studied via clinical trials.

Chai-Hu-Jia-Long-Gu-Mu-Li-Tang for Depression Treatment

To analyze the clinical evidence for CLM in depression, researchers conducted a systematic review and meta-analysis of 24 randomized controlled trials with over 2300 patients.

They also used network pharmacology techniques to identify potential active compounds in CLM and how they may work.

The meta-analysis showed that CLM alone or combined with an SSRI antidepressant:

  • Led to significantly higher recovery rates than SSRIs or SNRIs alone
  • Reduced depressive symptoms on scales like the Hamilton Depression Rating Scale (HAM-D) significantly more than antidepressants alone
  • Decreased anxiety symptoms on scales like HAMA more than antidepressants
  • Improved sleep based on the Pittsburgh Sleep Quality Index more than antidepressants
  • Had significantly fewer side effects like dizziness and dry mouth than antidepressants alone

These clinically relevant findings suggest CLM could provide substantial benefits beyond standard medications for a range of depression-related symptoms.

How Chaihu-jia-Longgu-Muli-tang May Work for Depression (Mechanisms of Action)

To uncover CLM’s potential mechanisms of action, the researchers first identified 129 active compounds in the 11 herbs that make up the formula.

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They then mapped 416 genes targeted by these compounds and found significant overlap with genes associated with depression.

Further network analysis pointed to several key pathways CLM may modulate to treat depression:

Inflammation:

  • CLM lowered inflammatory markers like IL-6 and TNF-alpha, which are often elevated in depression
  • Pathway analysis highlighted modulation of NF-kB, a key inflammatory pathway

Synaptic Plasticity:

  • Many identified targets play roles in synaptic function and neuroplasticity
  • May alleviate rigid negative thinking patterns via effects on synapses

Apoptosis:

  • Targets like AKT1 promote neuronal survival and prevent cell death
  • Could counteract brain volume loss and neuron damage in depression

The researchers suggest the combination of modulating inflammation, plasticity, and apoptosis may underlie CLM’s clinical benefits for depression and explain its advantages over single-target drugs like SSRIs.

Other Potential Mechanisms: PIK3R1, MAPK3, and AKT1

Further analysis pointed to three key protein targets that appear most relevant for CLM’s antidepressant effects:

PIK3R1:

  • Top predicted target of active compound stigmasterol
  • Part of the PI3K/AKT pathway, which regulates inflammation, plasticity, and neuronal survival

MAPK3:

  • Involved in synaptic plasticity and neuron function
  • Blocking MAPK signaling can mimic antidepressant effects

AKT1:

  • Powerful pro-survival protein that counters apoptosis and inflammation
  • Akt activation in the brain alleviates depressive behaviors in animal models

Molecular modeling indicated compounds like stigmasterol bind strongly to these proteins, suggesting they may be key targets underlying CLM’s antidepressant mechanisms.

Traditional Chinese Medicine as an Antidepressant: Untapped Herbs?

This rigorous analysis of a traditional Chinese medicine formula provides compelling clinical and mechanistic evidence for the possibility of developing new antidepressant treatments from these untapped resources.

While many herbal medicines are not well-researched, some formulations like CLM show great promise and appear to work via diverse synergistic mechanisms not seen with conventional single-target medications.

Future research should continue to bridge the gap between traditional medical systems and modern clinical science.

Although more work is still needed, this study helps pave the way for CLM and similar herbal medicines to be integrated into psychiatry as evidence-based complementary treatments.

With depression rates spiking due to COVID-19 stressors, exploring these safe, natural therapeutic options could provide much-needed help to millions struggling with mood disorders worldwide.

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