13 1 Vascular risk factors for depression and apathy Depression diagnostic criteria (DSM-5) The individual must be experiencing five or more symptoms during the same 2-week period and at least one of the symptoms should be either (1) depressed mood or (2) loss of interest or pleasure (core criteria). Collectively, these symptoms must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning 1. Depressed mood most of the day, nearly every day. 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day. 3. Significant weight loss when not dieting or weight gain, or decrease or increase in appetite nearly every day. 4. Insomnia or hypersomnia nearly every day. 5. A slowing down of thought and a reduction of physical movement (observable by others, not merely subjective feelings of restlessness or being slowed down). 6. Fatigue or loss of energy nearly every day. 7. Feelings of worthlessness or excessive or inappropriate guilt nearly every day. 8. Diminished ability to think or concentrate, or indecisiveness, nearly every day. 9. Recurrent thoughts of death, recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide. Vascular depression or a depressive-executive subtype of late-life depression? This clustering of vascular risks, vascular disease and depression in later life that clinicians frequently observed was confirmed in large epidemiological studies of late-life depression, whose findings prompted research into the potential relationships between depression and cardio- and cerebrovascular disease 13. Objectives were to try and confirm that depression was a causal risk factor for vascular disease, and to identify the underlying pathophysiological mechanisms of this relationship. Another field of research focused on questions regarding the causes and consequences of the raised risk of a depressive disorder in post-myocardial infarction 14 and post-stroke patients 15. Could it be that, not only recognized but also unrecognized or ‘silent’ vascular disease was a risk factor for and even a cause of late-life depression, and, if so, through what mechanisms? Neuroimaging studies showed an association between white matter hyperintensities (WMH), a marker of cerebral small vessel disease (CSVD; for more details, see the CSVD and vascular apathy hypothesis section), and depression 16. Clinically, CSVDrelated depression was linked to executive dysfunction and therapy resistance, leading to the inception of the vascular depression hypothesis 17. The proposed pathophysiological mechanism for this vascular subtype of depression was disruption of the fronto-striatal pathways of the brain by CSVD 17.