Addressing Cognition in Depression


Combination buspirone and melatonin exert therapeutic cognitive effects that are distinct from their antidepressant effects, according to a recent study.


Combination buspirone and melatonin exert therapeutic cognitive effects that are distinct from their antidepressant effects, according to a recent study.1

To identify whether residual cognitive deficits in patients with MDD may be independent of core MDD symptoms, the researchers revisited data from a previous study showing that combination buspirone-melatonin was more effective than buspirone monotherapy or placebo in managing depression symptoms.2

In addition to the Hamilton Depression Rating Scale, other scales used in that study included the clinical global impression of severity/improvement scale (CGI-S/I), the Inventory of Depressive Symptomatology 30-item version (IDSc30), Quick Inventory of Depressive Symptoms 16-item (version QIDS-SR16), and the Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ). The CGI-S/I and IDSc30 are physician rating scales and the QIDS-SR16 and CPFQ are patient-rating scales.

Data from the CPFQ formed the basis of the current study. Specifically, changes in symptoms assessed in the CPFQ were compared in treatment responders and nonresponders.

The original study was a 6-week, double-blind, placebo-controlled, randomized trial that compared buspirone 15 mg plus melatonin-SR 3 mg,  buspirone monotherapy, and placebo in 142 patients who met DSM-IV-TR criteria for MDD. At the end of the trial, scores on the GCI-I and IDSc30 were significantly better (P < .05) for patients receiving combination therapy than for patients receiving monotherapy and placebo. Improvements in scores on the QIDS-SR16 and CPFQ did not reach statistical significance. However, as mentioned, data for the CPFQ were later reexamined in relation to treatment responders and nonresponders. 

The physical dimension of the CPFQ assesses sleepiness and fatigue, and the cognitive dimension assesses apathy, inattention, forgetfulness, word-finding difficulties, and mental slowness. Patients grade the perceived quality of their physical and cognitive functioning for the past month on a 6-point scale.

Of 113 patients for whom CPFQ and IDSc30 data were available, 45 were treatment responders. Twenty-five were receiving combination therapy, 9 monotherapy, and 11 placebo. A significantly greater improvement (P < .0001) on total CPFQ scores was seen in these responders regardless of treatment assignment compared with the 72 nonresponders. However, combination therapy trended toward having a better impact on CPFDQ scores than monotherapy or placebo (ANCOVA: P = .05).

Because cognition can independently improve when mood improves, the researchers solely focused on nonresponders to isolate findings on improvements in cognition. They found that the total CPFQ cognitive dimension score favored the combination treatment over monotherapy and placebo. Marked improvement was seen in relation to word-finding difficulties, forgetfulness, mental slowness, and apathy.

These findings, which are preliminary, suggest that combination buspirone-melatonin therapy may benefit cognitive function in a way separate from its impact on mood symptoms.  The findings also suggest that some cognitive deficits in MDD may warrant treatment beyond that provided by an antidepressant agent.


1. Targum SD , Wedel PC , Fava M. Changes in cognitive symptoms after a buspirone melatonin. Combination treatment for Major Depressive Disorder. J Psychiatr Res. 2015 May 9. [Epub ahead of print]
2. Fava M, Targum SD, Nierenberg AA, et al. An exploratory study of combination buspirone and melatonin SR in Major Depressive Disorder (MDD): a possible role for neurogenesis in drug discovery. J Psychiat Res. 2012;46(12):1553-1563.

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