New study demonstrates the effects of magnesium combined with fluoxetine for depression

Major depressive disorder is frequently accompanied by cognitive impairment, including deficits in attention, memory, and executive function. Although selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine effectively improve depressive symptoms, cognitive recovery often lags behind mood improvement. A recently published randomized clinical trial evaluated whether oral magnesium supplementation could enhance cognitive recovery when used alongside fluoxetine therapy.

The six-week study included 40 adults with depression who were randomized to receive either fluoxetine alone or fluoxetine with 350 mg of magnesium daily. Cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA) and brain-derived neurotrophic factor (BDNF) was also measured.

Both groups demonstrated improvements in cognitive performance over the six-week intervention. However, participants receiving magnesium experienced significantly greater improvements, with average MoCA scores increasing by 4.8 points compared with 1.35 points in the fluoxetine-only group. The largest gains were observed in attention and memory, two cognitive domains commonly impaired in depression.

Although serum BDNF concentrations did not significantly differ between groups, changes in BDNF were more strongly correlated with cognitive improvements among participants receiving magnesium. This suggests that magnesium may enhance the relationship between neuroplasticity and cognitive recovery even when measurable circulating BDNF concentrations remain unchanged over a relatively short intervention period.

Several mechanisms may explain these findings. Magnesium serves as a cofactor in hundreds of enzymatic reactions and plays an essential role in neuronal signaling. It modulates NMDA receptor activity, supports synaptic plasticity, and promotes normal glutamatergic neurotransmission, all of which are critical for learning, memory, and long-term potentiation. These actions may complement fluoxetine by supporting the neuroplastic processes involved in cognitive recovery.

Overall, these findings suggest that magnesium supplementation may serve as an adjunct to antidepressant therapy.

By Michael Jurgelewicz, DC, MS, CNS, LDN

Source: Noor NJ, Syamsuddin S, Liaury K, et al. Effects of magnesium supplementation on serum brain-derived neurotrophic factor levels and cognitive function in patients undergoing fluoxetine therapy for depression. East Asian Archives of Psychiatry. 2026;36:75-80.

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