Table 2.

Key considerations for investigations of pharmacological interventions which target cognitive impairment in depression.

Pseudo-specificity	Description:	Indirect gains in cognitive performance due to changes in affective processing or motivation.
	Considerations:	• Statistical factor analysis to determine that cognitive change is independent of affective gain. • Use of relevant measures of affect and motivation, not only symptom-based outcome measures (e.g. BDI, MADRS).
Consistency of translation	Description:	Translation of cognitive effect between healthy and depressed populations is not always observed.
	Considerations:	• Establishing translational biomarker models of cognitive treatment response. • Use of cognitive outcome measures which have greater sensitivity to cognitive change in healthy populations.
Heterogeneity of cognitive impairment	Description:	Cognitive impairment manifests differently for every individual with MDD, which has implications for the therapeutic utility of drugs which target specific domains of cognition.
	Considerations:	• Consider subgroup analysis of patient clusters based on cognitive presentation if samples provide adequate power. • Consider recruitment of samples with specific cognitive presentation.
Discrepancies in cognitive measurement	Description:	Non-uniform approach to cognitive domains assessed across research studies, particularly regarding the differential use of objective and subjective measures of cognition.
	Considerations:	• Adopt a uniform approach to measurement; standardised battery of tasks appropriate for the heterogeneous profile and functional consequences of cognitive impairment in MDD. • Consider a combination of both objective and subjective cognitive outcome measures.
Therapeutic specificity	Description:	Conditions necessary for successful clinical use of agents which target cognition. In particular, whether efficacy is only seen in individuals who are currently depressed, or also in those at risk of depression and/or with remitted depression.
	Considerations:	• Identify whether agents should be used as prevention or treatment. • Identify whether treatment should be given during active episodes or to treat residual impairments during remission.