Electroconvulsive therapy (ECT) is an effective, fast-acting, and safe treatment for severe depression [
1], but it is associated with troublesome cognitive side effects across episodic memory, attention, and executive functions that persist for weeks [
2,
3] to months after treatment completion [
4,
5]. Such cognitive side effects of ECT are the greatest impediment to its prescription for depression, making it reserved for only the most severely ill patients [
6]. Therefore, novel treatments that counteract these side effects have the potential to improve current treatment strategies by allowing a greater number of severely ill patients to get earlier and more effective treatment with fewer cognitive side effects. However, research efforts into identification of methods to attenuate the cognitive side effects of ECT treatment without hampering its clinical efficacy have thus far been unsuccessful [
7].
Erythropoietin (EPO) is a promising treatment for cognitive dysfunction in mood disorders [
8,
9] and for counteracting ECT-induced cognitive side effects. EPO is not only produced systematically in the kidneys, but is also produced in the brain, where it mediates neuroprotection and development, modulates oxidative stress and inflammation [
10], and plays a key role in cognitive functioning [
11,
12]. Systemically administered EPO crosses the blood-brain barrier and has been shown in preclinical studies to mediate neuroprotection and neuroplasticity and to enhance cognitive functions when given in high doses (≥ 500 IU/kg body weight) [
13,
14]. Randomized controlled clinical studies suggest that 8–12 weeks of systemically administered high-dose (40,000–48,000 IU) EPO improves attention, memory, and executive functions in patients with treatment-resistant depression (TRD) [
9], bipolar disorder (BD) [
8], multiple sclerosis [
15], or schizophrenia [
16]. The cognitive benefits of EPO treatment seem to result from direct neurobiological actions rather than non-specific changes in red blood cells. For example, randomized placebo-controlled functional magnetic resonance imaging (fMRI) studies by our group [
17,
18] showed that a single high dose (40,000 IU) of EPO vs. placebo enhanced memory-relevant prefrontal and hippocampal activity in healthy and depressed individuals without affecting red blood cells. Consistent with this, our subsequent randomized, placebo-controlled trials revealed that eight weekly infusions of high-dose (40,000 IU) EPO vs. saline had mood-independent beneficial effects on cognitive function in patients with TRD (
N = 40) and BD in remission (
N = 44) [
8,
9]. These cognitive benefits were accompanied by EPO-associated increase in neural activity within the frontal and the parietal lobes during strategic encoding and working memory tests [
8,
9,
19]. Notably, EPO-related memory improvement in these patients was associated with reversal of hippocampal (cornu ammonis 1–3) and subiculum volume loss [
20], which is interesting in light of ECT induction of hippocampal volume increase (see, e.g., [
21]). Importantly, these brain changes were independent of changes in mood and lasted long term beyond red blood cell normalization. Several neurobiological actions may underlie these beneficial cognitive effects of EPO treatment, including activation of anti-inflammatory, anti-apoptotic, and antioxidant signaling pathways [
14,
22,
23] and growth of dendrites, maturation of neural progenitor cells, and upregulation of brain-derived neurotrophic factor (BDNF) [
24,
25]. Taken together, preliminary findings highlight EPO as a candidate treatment for ECT-induced cognitive deficits in mood disorders. This trial extends our previous work by investigating for the first time whether adjunctive EPO treatment can counteract the cognitive side effects of ECT.
Aims and hypotheses
The present trial aims to investigate whether one primer infusion of EPO/saline before ECT followed by three weekly EPO/saline infusions during the course of ECT counteracts cognitive side effects in patients receiving ECT. Furthermore, we aim to investigate the neuronal underpinnings of such potential effects of EPO with structural and functional magnetic resonance imaging (MRI) and the role of oxidative, inflammatory, and neuroendocrinological systems with blood and urine tests.
We hypothesize that EPO treatment will (1) counteract ECT-induced decline in cognition (primary endpoint), which will be accompanied by (2) increased subregional hippocampal volume, (3) greater memory-related hippocampal activation and reinforcement of dorsolateral prefrontal activity during memory encoding and working memory, and (4) changes in peripheral markers of inflammation, oxidative stress, and neuroplasticity. Given preliminary evidence for the beneficial effects of EPO on depression-relevant outcomes [
8,
13], a secondary hypothesis is that add-on EPO treatment will produce greater, more sustained mood improvement than ECT treatment alone.