Towards understanding and treating anhedonia in depression: investigating the neuropsychological effects of losartan in Behavioural Activation

Aims -

I am proposing a double-blind randomised controlled trial to investigate whether losartan can improve the efficacy of Behavioural Activation (BA) for individuals with high levels of anhedonia, as observed through neuropsychological markers. Background -

Depression is a common mental illness characterised by low mood or anhedonia. Recommended treatments have been found to reduce symptoms in ~54% to 62% of cases, but many individuals do not benefit from treatment, and rates of relapse and recurrence are high (Vittengl et al., 2009; Cujipers et al., 2020). Anhedonia (~37-72% prevalence in major depressive disorder (MDD); Pizzagalli, 2022) - the loss of pleasurable feelings or reactions to previously rewarding stimuli (Tolentino & Schmidt, 2018) - is associated with poor outcomes, including severe depressive symptoms and resistance to treatment (Kelly et al., 2022; Pizzagalli, 2022).

BA - recommended by the National Institute for Health and Care Excellence for moderate and severe depression (2022) - uses positive reinforcement to increase patients' engagement with rewarding behaviours (Ekers et al., 2007). BA can be effective across varied populations and in some cases has proved more effective than other standard treatments (Forbes et al., 2020; Uphoff et al., 2020).

However, treatment outcomes vary, and the mechanisms behind this are not fully understood (Forbes, 2020; Uphoff et al., 2020). One possibility is that the presence and severity of anhedonia may impact BA efficacy - patients with anhedonia may not experience pleasure from the rewards introduced through BA, thus undermining the incremental behavioural mechanism (Webb et al., 2022).

Reward processes, evaluated using neuropsychological tasks and neuroimaging, have been found to be disrupted in MDD, and especially in those patients with high levels of anhedonia (Rizvi et al., 2015). Reward processes are underpinned by separate but overlapping neurobiological processes, involving the striatum and dopaminergic (DA) pathways (Pizzagalli, 2022), and neuroimaging studies have found abnormalities in anhedonia in relation to different reward processes.

For example, reduced ventral striatal response to reward prediction was found to be associated with anhedonia, while larger reward learning signals in the ventral striatum predicted lower anhedonic traits after six months (Kumar et al., 2018; Borsini et al., 2020; Pizzagalli, 2022). Using neuropsychological methods, improved performance in reward processing tasks may indicate an improved clinical response to reward-focused interventions, like BA.

Preliminary research has shown that the renin-angiotensin system - a complex system involved in blood pressure maintenance - may be implicated in reward processing (Pulcu et al., 2019). Initial findings have shown that angiotensin receptors modulate striatal DA release in reward-related behaviours (Narayanaswami et al., 2013). Losartan - an angiotensin-II receptor antagonist that is used to treat hypertension - has been found to increase the activation of the excitatory DA D1 receptor (Liu et al., 2012).

Furthermore, Dr Reinecke's work shows that only a single dose of the medication shifts learning from loss to reward outcomes in humans (Pulcu et al., 2019), and pilot data suggests such a shift may be even more pronounced in dysphoric patients (Figure 1). Accordingly, losartan may facilitate DA transmission in reward processing domains, leading to improved efficacy of BA, as measured by an improved response to neuropsychological reward tasks.