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Table 2 Pharmacological sleep interventions in clinical trials for Alzheimer’s disease

From: Proteostasis failure exacerbates neuronal circuit dysfunction and sleep impairments in Alzheimer’s disease

Relevance to proteostasis

Approval, usage

# Trials (# Ongoing)

Clinicaltrials.gov Identifier / trial results (if reported)

Orexin antagonists (inc. lemborexant, suvorexant, seltorexant)—Orexinergic signaling promotes wakefulness; blocking the orexin receptor promotes sleep (see Fig. 4) [18, 184]

 • While not a major contributor, orexinergic impairments occur in AD

 • Vulnerable to tau pathology and likely potentiates AD-related sleep deficits

 • Orexin-A neuropeptide regulates (enhances or decreases depending) autophagy via OXR1 signalling [305,306,307]—potential for synergistic sleep-proteostasis benefits of orexin antagonism in AD

 • Potential Experimental Use—treatment can be used to assess how tau imparts cell autonomous autophagic deficits, and if rescuing orexin function and/or promoting sleep improves tau clearance

Insomnia (lemborexant, suvorexant), sleep disturbances in AD (suvorexant)

4 (2)

NCT02750306 – Phase 3, suvorexant, insomnia in AD; significant improvements in total sleep time vs. placebo; results published: [308]

NCT03001557 – Phase 2, lemborexant, irregular sleep–wake rhythm disorder and mild-to-moderate AD; primary outcomes assessed a wide variety of sleep parameters; overall, no strong benefit on sleep, some significant reduction of restlessness in treated groups vs. placebo

No results—NCT04629547b

No results—NCT05307692b

Melatonin (inc. circadin, piromelatine, ramelteon)Hormone balances circadian rhythmicity [309,310,311] (see Fig. 4)

 • Hormone released from the pineal gland

 • Mediates regulation of circadian rhythms and promotes sleep

 • Potential Experimental Use—used to probe interaction between sleep/biological clock disruptions with autophagic deficits (see Fig. 4)

 • Melatonin in AD may simultaneously improve sleep and proteostasis

Oral/dietary supplement for sleep

5 (1)

NCT00940589 – Phase 2, circadin (prolonged-release melatonin), mild-to-moderate AD; cognition (↑MMSE, ↔ ADAS-Cog) improved sleep (↑PSQI), and behavior (↑IADL) [312]

NCT00000171 – Phase 3, melatonin, AD; primary sleep measures not statistically significant (nocturnal sleep time), trend for nocturnal sleep improvements [313]

NCT02615002 – Phase 2, piromelatine (multimodal melatonin receptor and serotonin receptor agonist), AD; GWAS identified a 6 SNP cluster in chromosome 2q12 which predicted efficacy of treatment: non-carriers improved on ADAS-Cog14 and PSQI, carriers declined on these but improved on cNTB (both compared to placebo); results published: [314]

No results—NCT00325728

No results—NCT03954899a,b

GABA enhancement (inc. zolpidem (Ambien), sodium oxybate, allopregnanolone)Increases or modulates GABAergic activity, can promote sleep (see Fig. 4) [315]

 • Optogenetic stimulation of GABAergic interneurons increases autophagy (i.e., Beclin1 and LC3 levels) and reduces Aβ in an AD mouse model [316]

 • Allopregnanolone enhances autophagy (↑ LC3B-II and ↓ SQSTM1), neuroprotective in a rat glaucoma model [317]; potential synergistic effect of GABAergic modulation on improving sleep and proteostasis in AD

 • Critically, GABAergic dysfunction is a major part of AD progression; reviewed in [203]

Zolpidem—Insomnia

Sodium Oxybate—narcolepsy

Allopregnanolone—postpartum depression

4 (1)

NCT00814502 – zolpidem CR, AD, or vascular dementia; small sample size limitation (8 zolpidem CR, 9 placebo), no changes or trend in primary outcomes (sleep efficiency and time)

NCT03075241 – Phase 3, zolpidem and zoplicone (separately), insomnia in AD; 81 min increase in nocturnal sleep (zoplicone only), reduced night-time awakenings and length (either zolpidem or zoplicone), compared to placebo; results published: [318]

No results—NCT00706186

No results—NCT03748303b

Antihistamines—Inhibit histaminergic signalling in the tuberomammillary nucleus of the lateral hypothalamus (+ peripheral effects); blocks arousal and promotes SWS, but not REM (see Fig. 4) [18, 319]

 • Could be an effective therapeutic factor in the treatment of AD through the antagonists against H3R and regulation of H2R

 • Specific mechanism in protein clearance is yet to be investigated [320]

Allergies, insomnia

3 (0)

NCT01548287 – Phase 2, AZD5213, sleep in MCI and mild AD; no clear benefit in primary outcome (total sleep time)

NCT01028911 – Phase 1, PF-03654746 and donepezil, mild-to-moderate AD; no serious adverse events, 5/7 participants in treatment group experienced non-serious adverse events

No results—NCT01009255

Adrenergic agonist (dexmedetomidine)Inhibits noradrenergic release (notably in the LC), decreasing arousal [321, 322]

 • Binds pre-synaptic α2 adrenergic receptors—hyperpolarizing LC neurons and ↓ noradrenergic release—↑ EEG slow wave oscillations [321, 322] & ↑ glymphatics [323]

 • Dexmedetomidine ↑ glymphatic flow—effective adjuvant to improve intrathecal drug delivery in mice [323]

 • Adrenergic agonism can impact sleep & proteostasis via glymphatics. However, dexmedetomidine is commonly used as an analgesic and sedative, potentially limiting sleep quality

Sedation

No results—NCT04205539 – no results; withdrawn prior to enrollment

- pending COVID-19 pandemic

mTOR inhibitor (rapamune)Multiple signalling targets, may modulate sleep in AD through autophagy induction [1]

 • Compared to the other therapies in this table, rapamune induces ubiquitin proteasomal and autophagic-lysosomal systems directly, but not selectively

Potential Experimental Use—enhancing proteostasis to reduce proteinopathies that reduce sleep

Immunosuppressant

1 (1)

No results—NCT04200911b

Anti-fatigue (modafinil)Dopamine reuptake inhibitor: dopamine helps regulate circadian rhythmicity and REM (notably in Parkinson’s disease and REM sleep behavior disorder) [324,325,326]

 • Modafinil—activates PI3K/Akt/mTOR/P70S6K signalling

 • Suppresses excessive autophagy and apoptosis of hippocampal neurons as a result of sleep deprivation—rescue of aberrant proteostasis from sleep impairment [327]

Obstructive sleep apnea, narcolepsy

1 (0)

NCT00626210 – modafinil; limited results because study was terminated early (low enrollment: 2 participants)

Cannabis and endocannabinoid system, i.e. cannabidiol (inc. nabilone)Endocannabinoid system regulates circadian-control of physiological processes (inc. sleep) [328, 329]

 • ↑ Aβ degradation genes ACE1, IDE and ECE1 and heat shock proteins – may ↓ tau and Aβ misfolding

 • Further research required to understand mechanisms, i modification of phosphorylation pathways, and alterations of glial reactivity or Aβ load [330, 331]

Epilepsy, common usage (i.e., for anxiety, pain)

4 (3)

NCT02351882 – Phase 2 and 3, nabilone, moderate-to-severe AD; beneficial effects of nabilone on agitation and neuropsychiatric assessment despite higher sedation; sleep not directly assessed; results published: [332]

No results—NCT04516057b; NCT04436081b; NCT05239390b

Serotoninergic modulators and anti-depressants (inc. trazodone, nelotanserin, sertraline (Zoloft), escitalopram oxalate)reduces REM sleep and increases wakefulness [171, 333]

 • Serotonergic signaling in conjunction with UPRmt (mitochondrial specific unfolded protein response), facilitates communication of proteotoxic stress from neuronal mitochondria to peripheral tissue and helps establish a mechanistic link between remodeling of mitochondrial function by a biogenic amine and metabolic disturbances seen in neurodegenerative conditions [334]

 • Potential Experimental Use—role for secretion of serotonin in cell-non-autonomous communication of mitochondrial stress [334]

 • Trazodone reverses the low protein synthesis rates associated with elevated phosphorylated-eIF2α levels, an effect commonly seen with overactive UPR and in NDDs [275, 276]

Depression, anxiety;

Trazodone—off-label for sleep disturbances in AD

11 (2)

NCT00895895 – Phase 2, SAM-531, mild-to-moderate AD; no differences in primary outcome (ADAS-Cog), some sporadic significance in secondary outcomes, trend to benefit in NPI (inc. sleep behaviors) at 3 mg dose but not directly tested for sleep

NCT02708186a – Phase 2, nelotanserin, REM sleep behavioral disorder in DLB/PDD; no differences vs. placebo in REM behavioral disorder-associated movements; results published: [333]

NCT01142258 – Phase 3, trazodone, sleep disorder in AD; Trazodone increased night-time sleep by 42.5 min with no effect on daytime sleepiness or cognition; results published: [335]

NCT00009191 – Phase 4, sertraline, depression in AD; reduced depressive symptoms, sleep not assessed; results published: [336]

No results—NCT01841125; NCT01867775; NCT00519298; NCT02871427; NCT00103649; NCT05282550a,b; NCT05004987b

Anti-psychotics (inc. aripiprazole, risperidone) and anti-convulsants (inc. gabapentin enacarbil, levetiracetam)Less sleep related, drowsiness as a side effect;

Note: Gabapentin Enarcarbil is a GABA agonist [337]

 • Limited link to proteostasis

 • Broad neurotransmitter receptor modulation may have non-specific effects as described in more specific rows above

Various uses (i.e., bipolar disorder, schizophrenia, epilepsy, restless legs disorder; anti-convulsant)

8 (2)

NCT01438060 – Phase 3, aripiprazole, AD with psychotic symptoms; no obvious changes in NPI sleep score (secondary outcome), no significant change in NPI psychosis (primary outcome)

NCT02002819 – Phase 2, levetiracetam, AD; some cognitive benefits, sleep not a primary or secondary outcome; results published: [338]

NCT00208819; NCT02078310; NCT00232570; NCT04341467b – no results (anti-psychotics)

No results—NCT03790709; NCT03082755b (anti-convulsants)

Other dietary supplements (inc. citicoline, probiotics)—citicoline – increased choline levels for acetylcholine synthesis, cholinergic signalling from PPT/LDTT and basal forebrain involved in REM sleep and wakefulness (reviewed in [339]); probiotics – likely indirect benefits on sleep from anti-oxidant and anti-inflammatory effects [340]

 • Limited direct relevance to proteostasis

Citicoline – potential benefits of supplementation in aging-related cognitive decline [341];

Probiotics – various uses

2 (2)

NCT05200208b (citicoline)

No results—NCT05145881b (probiotics)

  1. Studies indicated as “results available” have results posted on clinicaltrials.gov, or a publication indexed in clinicaltrials.gov by NCT identifier
  2. AD Alzheimer’s disease, ADAS-cog Alzheimer’s Disease Assessment Scale–Cognitive Subscale, cNTB Computerized neuropsychological test battery, DLB Dementia with Lewy bodies, eIF2α Eukaryotic initiation factor 2α, GWAS Genome-wide association study, IADL Instrumental activities of daily living, LC Locus coeruleus, PPT/LDT Pedunculopontine and laterodorsal tegmental nuclei, MCI Mild cognitive impairment, MMSE Mini-Mental State Examination, NDD Neurodegenerative disease, NPI Neuropsychiatric Inventory, PDD Parkinson’s disease dementia, PQSI Pittsburgh Sleep Quality Index, REM Rapid eye movement, SNP Single-nucleotide polymorphism, SWS Slow wave sleep, UPR Unfolded protein response
  3. aRefers to non-AD studies that were included in the search and considered relevant (MCI, aging, or broad/other dementia)
  4. bRefers to ongoing studies with clinicaltrials.gov status “Not yet recruiting”, “Recruiting”, “Enrolling by invitation”, or “Active, not recruiting”