Identifying the neuropsychiatric health effects of low-dose lithium interventions: A systematic review

Neuropsychiatric disorders, including depression, bipolar disorder, and cognitive decline, are among the leading causes of disability worldwide. While lithium is a well-established treatment for mood stabilization, its long-term use at standard doses is linked to serious side effects like kidney and thyroid dysfunction. In their systematic review, Strawbridge et al. explore whether low-dose lithium (LDL) could offer similar mental health benefits without the risks in their study, Identifying the Neuropsychiatric Health Effects of Low-Dose Lithium Interventions: A Systematic Review. By analyzing 16 clinical studies, they examined LDL’s impact on depression, mania, suicidality, and cognitive function, revealing promising results for brain health and mood stabilization, though more research is needed.

Lithium has been a trusted treatment for bipolar disorder and depression for decades. Doctors prescribe it to stabilize mood swings, reduce suicidal thoughts, and prevent relapse in people with mood disorders. However, high-dose lithium can cause serious side effects, including kidney damage, thyroid dysfunction, and cognitive impairment. Because of this, many people avoid lithium despite its benefits.

But what if a lower dose of lithium could provide some of the same benefits without the harmful side effects? Scientists have recently started studying low-dose lithium (LDL), which is defined as a serum lithium level of 0.6 mmol/L or lower.

The main questions researchers want to answer are:

• Can LDL improve depression or mood disorders without the risks of standard lithium?
• Does it have neuroprotective effects, meaning it could slow cognitive decline in people with Alzheimer’s disease or mild cognitive impairment (MCI)?
• Could LDL reduce suicide risk like high-dose lithium does?

This systematic review analyzed 16 clinical studies to see if LDL could be a safe and effective treatment for mental health conditions.

“We aimed to synthesize all available evidence from interventional studies investigating low-dose lithium across neuropsychiatric outcomes.”

The findings were mixed but promising, suggesting that LDL could be useful for some conditions, especially cognitive disorders and mood stabilization.

To find reliable research, the authors followed PRISMA guidelines, a standard method for systematic reviews. They searched databases like PubMed, Embase, and PsycINFO for studies involving low-dose lithium in adults.

To be included in this review, a study had to:

1. Involve human participants (not animal studies).
2. Use low-dose lithium as the main treatment.
3. Measure mental health or cognitive outcomes (such as depression, mania, suicidality, or cognition).
4. Include before-and-after treatment comparisons or compare LDL with a placebo or another treatment.
5. 
   

“A total of 18 articles were examined and grouped according to outcome domain (cognition, depression, mania, and related constructs, e.g., suicidality).”

After analyzing over 3,400 studies, researchers selected 16 studies that met all the criteria. These studies focused on bipolar disorder, depression, cognitive impairment, and suicidality.

The effect of LDL on depression was mixed. Some studies showed positive results, while others found no significant improvement. In two studies, LDL was found to improve treatment-resistant depression (TRD) when used as an add-on therapy to existing antidepressant treatments. 

However, not all studies reached the same conclusion. Some found no major differences between LDL and placebo when treating depression. This suggests that while LDL might benefit certain patients, it is not a guaranteed solution for everyone. Researchers believe LDL may work best as an adjunct therapy rather than as a standalone treatment for depression.

“Significant benefits (versus placebo) were identified for attenuating cognitive decline and potentially as an adjunctive therapy for people with depression/mania.”

For mania and bipolar disorder, LDL was less effective than standard lithium doses. In patients experiencing an acute manic episode, LDL did not significantly reduce mania symptoms compared to placebo. This suggests that LDL is not strong enough to manage severe mood episodes on its own.

However, one study found that LDL helped prevent future mood episodes in stable individuals with bipolar disorder. Another study reported remission rates of 21% for acute mania when treated with LDL, compared to only 7% in the placebo group (Stokes et al., 1976). These findings suggest that LDL might be useful for long-term mood stabilization but is not effective for treating active mania.

“LDL was associated with a shorter time to recurrence of any mood episode compared to those taking standard-dose lithium.”

One of the most promising findings of this review was LDL’s potential to protect brain function and slow cognitive decline. Patients with Alzheimer’s disease and mild cognitive impairment (MCI) who received LDL performed better on memory tests compared to those given a placebo.

One study found that LDL improved cognitive performance in patients with MCI (Nunes et al., 2013). Another study discovered that LDL helped slow the progression of Alzheimer’s disease over five years (Forlenza et al., 2019). Researchers believe this effect may be due to lithium’s ability to protect brain cells and reduce inflammation, both of which are linked to cognitive decline.

“LDL’s apparent pro-cognitive effects and positive safety profile open promising avenues in the fields of neurodegeneration.”

Although high-dose lithium is known to reduce suicide risk, there has been very little research on whether LDL has the same effect. The few studies that investigated suicidality produced inconclusive results.

One study found that 30% of LDL patients had reduced suicidal thoughts, compared to only 15% in the placebo group (Khan et al., 2011). However, other studies did not show a significant reduction in suicidality with LDL treatment. Given that lithium in drinking water has been linked to lower suicide rates, researchers believe LDL may have a similar effect, but more studies are needed to confirm this.

“Despite the paucity and heterogeneity of studies, LDL’s potential to prevent cognitive/affective syndromes warrants further research.”

One of the most critical findings from this review was that LDL is much safer than standard lithium doses. Unlike high-dose lithium, which can cause kidney damage, thyroid problems, and cognitive impairment, LDL has very few reported side effects.

No significant safety concerns were found across any of the reviewed studies. LDL did not cause kidney or thyroid damage, making it a safer long-term option for patients who cannot tolerate high-dose lithium. Some studies even found that LDL had fewer side effects than placebo, suggesting it is highly tolerable for most people.

“Across studies, LDL was reported to be safe.”

This study suggests that LDL has exciting potential for mental health and cognitive disorders:

• Cognitive Protection: LDL could help prevent Alzheimer’s disease and dementia.
• Mood Support: It may be helpful as an add-on therapy for depression but not as a standalone treatment.
• Bipolar Disorder Management: LDL may help prevent relapses, but it is not strong enough to treat mania alone.
• Safer Long-Term Use: Lower doses mean fewer side effects, making LDL an appealing option for long-term treatment.

More large-scale studies are needed to confirm these benefits and determine the best dosage and treatment conditions.

Low-dose lithium could be a breakthrough treatment for depression, bipolar disorder, and cognitive decline—offering benefits without the risks of standard lithium. While not a one-size-fits-all solution, it shows strong brain protection and mood stabilization potential.

With more research, LDL could become a mainstream treatment for Alzheimer’s prevention, mood disorders, and even suicide prevention. It remains an exciting area of study that could transform mental health care.

What’s next? Scientists need more extensive, long-term studies to confirm LDL’s full potential. But if these findings hold up, low-dose lithium could revolutionize mental health treatment.