TAK-653 Reverses Core Depressive Symptoms in Chronic Stress-Induced Monkey Model

Abstract

Background: Major Depressive Disorder represents a prevalent and critical mental health issue that highlights the pressing need for innovative therapeutic solutions. Recent research has identified dysfunction within the glutamate system as a crucial element influencing both the onset and management of depressive symptoms. Although TAK-653 is a new positive allosteric modulator of AMPA receptors, its effects have not been rigorously examined in models of depression in primates. Methods: To assess its potential antidepressant properties, a chronic unpredictable mild stress protocol was implemented over 12 weeks to create a monkey model of depression, followed by a two-week treatment period with TAK-653. Results: Behavioral evaluations showed that following stress exposure, the monkeys exhibited reduced motivation for food, increased huddling, diminished movement, and a tendency to remain at the lower levels of their enclosure. They also displayed heightened anxiety in response to external stimuli. Plasma analyses indicated higher levels of cortisol, IL-6, and IL-8 in the stressed monkeys compared to baseline readings, confirming the efficacy of the stress-inducing protocol. Post-treatment with TAK-653 resulted in significant improvements, such as enhanced motivation for food, less huddling behavior, greater activity, and a move towards the upper areas of the enclosure. Additionally, the plasma analysis revealed a marked decrease in cortisol and IL-6 levels, along with an increased expression of BDNF. Conclusions: These findings indicate that TAK-653 effectively alleviates depression-like behaviors in nonhuman primate models, thereby paving the way for a promising new strategy in the treatment of depression.

Keywords: TAK-653; chronic unpredictable mild stress; cytokines; major depressive disorder; monkey.

Figure 1

Schematic representation of the experimental design. (A) The general timeline of the experiment. (B) The Chronic Unpredictable Mild Stress (CUMS) protocol was utilized on cynomolgus monkeys to create a model of Major Depressive Disorder (MDD). Subsequently, the antidepressant efficacy of TAK-653 was assessed in these depressed subjects, laying the groundwork for potential future clinical applications.

Figure 2

The increased anxiety levels following CUMS. (A) The normalized cortisol levels in plasma were measured before and after the CUMS intervention. The green circles represent the raw data, while the gray shaded regions denote the Baseline and CUMS conditions used for comparison. (B) A schematic representation of the HIT is provided. ① Profile pose: The intruder entered the room, standing 1 m away from the cage and maintained this distance for a duration of 2 min. ② Stare pose: The intruder then turned 90 degrees to face the monkey directly, maintaining eye contact for another 2 min without exiting the room. ③ Back pose: Next, the intruder turned 180 degrees to position themselves directly opposite the monkey for a continued period of 2 min while remaining present in the room. ④ Waving arm pose: Finally, the intruder rotated back towards the monkey and waved their arms for 2 min. (C) The cumulative duration of anxiety-like behaviors observed across the five poses is presented for baseline (blue) and after CUMS (red). (* p < 0.05, as determined by Tukey’s multiple comparisons test).

Figure 3

The antidepressant effects of TAK-653 on behaviors indicative of depression. (A) The frequency of attempts to access an apple over the three-day period. (B) The cumulative time spent in a huddled posture. (C) The overall duration of locomotor activity. (D) The total time spent hanging vertically. (E) The percentage of time spent at the bottom of the enclosure. (F) The percentage of time spent at the top of the enclosure. The three distinct colors and shapes correspond to three different subjects. (ns: p > 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, Tukey’s multiple comparisons test).

Figure 4

The variations in cortisol and inflammatory cytokines. (A) The normalized levels of cortisol. (B) The normalized levels of IL-1β. (C) The normalized levels of IL-4. (D) The normalized levels of IL-6. (E) The normalized levels of IL-8. (F) The normalized levels of IL-10. (G) The normalized levels of BDNF. (H) The normalized levels of TNF-α. The three distinct colors and shapes correspond to three different subjects. (ns: p > 0.05, * p < 0.05, ** p < 0.01, Tukey’s multiple comparisons test).