ALTO-100, previously known as NSI-189 (NeuralStem Inc. 189),[3] is a drug described as a hippocampal neurogenesis stimulant and indirect brain-derived neurotrophic factor (BDNF) modulator which is under development for the treatment of major depressive disorder (MDD), bipolar depression, and post-traumatic stress disorder (PTSD).

[3][6][7] However, it is thought to work through indirectly enhancing BDNF signaling and increasing neuroplasticity and neurogenesis in the hippocampus.

[4] Findings of the effectiveness of ALTO-100 in treating MDD in phase 1 and 2 trials have been mixed, although cognitive and memory improvements have been observed.

[20][21] Major mechanisms thought to contribute to these changes include prolonged exposure to stress (in part mediated by increased hippocampal glucocorticoid signaling), environmental deprivation, and physical inactivity, among others.

[24][29] On the basis of the preceding findings, enhancing hippocampal neurogenesis has been of interest for possible pharmaceutical treatment of depression.

[1][33][10] It is unknown whether the hippocampal volume increase exclusively represents neurogenesis or also includes neuropil augmentation.

[34][35] In a small phase 1 clinical study, ALTO-100 (40–150 mg/day) for 4 weeks had no impact on hippocampal or amygdalar volume measured by magnetic resonance imaging (MRI) in people with major depressive disorder.

[37][38] Early development of ALTO-100 was supported by the Defense Advanced Research Projects Agency (DARPA) and the National Institutes of Health (NIH).

[40] A phase Ib clinical trial for treating MDD in 24 patients started in 2012 and completed in July 2014, with results published in December 2015.

[10][41] In July 2017, it was announced that a phase II clinical trial with 220 patients failed to meet its primary effectiveness endpoint (MADRSTooltip Montgomery–Åsberg Depression Rating Scale) in MDD.

It revealed statistically significant improvements on patient-reported depression scales and in aspects of cognition for the 40 mg/day dose.

The study concluded that NSI-189 is effective as a safe adjunctive therapy, with the most significant antidepressant and pro-cognitive benefits noted in patients with moderate depression.

[46] In addition to MDD, Neuralstem had said that it has intended to pursue clinical development of NSI-189 for a variety of other neurological conditions, including traumatic brain injury, Alzheimer's disease, post-traumatic stress disorder, stroke, and to prevent cognitive and memory decline in aging.