Glymphatic system and psychiatric disorders: need for a new paradigm?

Tommaso Barlattani^1*Alessandro Cavatassi¹Antony Bologna¹Valentina Socci^1*Edoardo Trebbi²Maurizio Malavolta¹Alessandro Rossi¹Vassilis Martiadis³Carmine Tomasetti⁴Domenico De Berardis⁴Giorgio Di Lorenzo^5,6Francesca Pacitti⁷

• ¹University of L'Aquila, L'Aquila, Italy
• ²Universita degli Studi di Roma La Sapienza, Rome, Italy
• ³Azienda Sanitaria Locale Napoli 1 Centro, Naples, Italy
• ⁴Azienda Sanitaria Locale 4 Teramo, Teramo, Italy
• ⁵Universita degli Studi di Roma Tor Vergata, Rome, Italy
• ⁶Fondazione Santa Lucia Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy
• ⁷Universita degli Studi dell'Aquila, L'Aquila, Italy

Psychiatric disorders like depression, bipolar disorder, schizophrenia, and post-traumatic stress disorder have conventionally theorized on alterations in neurotransmitters, receptor pharmacodynamics, and neural connectivity. However, recent research points to a complementary framework involving the glymphatic system, a specialized glial lymphatic pathway that removes metabolic waste products, particularly during deep sleep, through the coordinated action of cerebrospinal fluid, interstitial fluid, and the aquaporin 4 channels of astrocytes. When the glymphatic network is compromised, neurotoxic proteins, such as beta-amyloid and tau, and inflammatory mediators can accumulate, potentially exacerbating insomnia, inflammation, and circadian disturbances. These same processes often occur in psychiatric disorders, fueling oxidative stress, neuroinflammation, and cognitive decline. New neuroimaging methods, such as diffusion tensor imaging and the analysis Along the Perivascular Space, ALPS, index, allow clinicians and researchers to quantify perivascular flow deficits in vivo. Preliminary evidence suggests that enhancing glymphatic function by improving sleep architecture, supporting astrocyte health, or scheduling drug delivery based on circadian fluctuations may offer clinical benefits. Here, we present an overview of glymphatic biology, examine its relevance to psychiatric pathophysiology, highlight findings from emerging neuroimaging studies, and consider ways modulating glymphatic flow may improve psychiatric pharmacotherapy.