**Nanosystems, Drug Molecule Functionalization and Intranasal Delivery: An Update on the Most Promising Strategies for Increasing the Therapeutic Efficacy of Antidepressant and Anxiolytic Drugs**

**Jéssica L. Antunes <sup>1</sup> , Joana Amado <sup>1</sup> , Francisco Veiga 1,2, Ana Cláudia Paiva-Santos 1,2,\* and Patrícia C. Pires 1,2,3,\***


**Abstract:** Depression and anxiety are high incidence and debilitating psychiatric disorders, usually treated by antidepressant or anxiolytic drug administration, respectively. Nevertheless, treatment is usually given through the oral route, but the low permeability of the blood–brain barrier reduces the amount of drug that will be able to reach it, thus consequently reducing the therapeutic efficacy. Which is why it is imperative to find new solutions to make these treatments more effective, safer, and faster. To overcome this obstacle, three main strategies have been used to improve brain drug targeting: the intranasal route of administration, which allows the drug to be directly transported to the brain by neuronal pathways, bypassing the blood–brain barrier and avoiding the hepatic and gastrointestinal metabolism; the use of nanosystems for drug encapsulation, including polymeric and lipidic nanoparticles, nanometric emulsions, and nanogels; and drug molecule functionalization by ligand attachment, such as peptides and polymers. Pharmacokinetic and pharmacodynamic in vivo studies' results have shown that intranasal administration can be more efficient in brain targeting than other administration routes, and that the use of nanoformulations and drug functionalization can be quite advantageous in increasing brain–drug bioavailability. These strategies could be the key to future improved therapies for depressive and anxiety disorders.

**Keywords:** anxiety; blood–brain barrier; brain bioavailability; depression; drug molecule functionalization; intranasal; nanoemulsions; nanoparticles; nanosystems; nose-to-brain

## **1. Introduction**

*1.1. Pathophysiology and Treatment of Depression and Anxiety Disorders: Current Aspects and Limitations*

Anxiety is a central nervous system (CNS) disorder characterized by tension, restlessness, and increased effort to concentrate, with a persistent depressed mood and lack of interest in activities which pleasure was once taken from. We can consider the existence of several types of anxiety disorders, such as disorders related to separation, social anxiety, panic, specific phobias, and generalized anxiety disorder. These disorders generally begin in childhood, adolescence, or early adulthood. The general physiological mechanism by which these types of disorders arise is related to the γ-aminobutyric acid (GABA), which is inhibited and, hence, does not fulfill its role in the downregulation of neuronal excitability. It is estimated to affect millions of people worldwide, leading to a great loss in a person's quality of life [1–7].

**Citation:** Antunes, J.L.; Amado, J.; Veiga, F.; Paiva-Santos, A.C.; Pires, P.C. Nanosystems, Drug Molecule Functionalization and Intranasal Delivery: An Update on the Most Promising Strategies for Increasing the Therapeutic Efficacy of Antidepressant and Anxiolytic Drugs. *Pharmaceutics* **2023**, *15*, 998. https://doi.org/10.3390/ pharmaceutics15030998

Academic Editor: Giuseppe De Rosa

Received: 25 February 2023 Revised: 9 March 2023 Accepted: 16 March 2023 Published: 20 March 2023

**Copyright:** © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

In turn, depression is the biggest public health problem, making it a common mental disorder and one of the world's leading causes of disability. In 2020, this disease affected about 16% of the world's population [8]. The etiology of depression has been related to stress. It is usually manifested by a loss of interest, feelings of guilt, depressed mood, sleep disturbance, low energy, and suicidal thoughts and attempts. There are several theories around the origin of depression, but the most accepted is the monoamine theory, which is related to a decrease in serotonin, noradrenaline, and dopamine levels in the CNS. It is caused by decreased excitability on the dopaminergic and/or serotonergic pathway. The markers of oxidative stress may also indicate depression, such as low levels of glutathione (GSH) and other antioxidants, and high levels of thiobarbituric acid (TBARS), F2 isoprostanes, inflammatory cytokines, and reactive oxygen species. Depression has also been associated with low levels of catalase, an enzyme responsible for the degradation of hydrogen peroxide into water and oxygen. In depressive situations, this enzyme is in deficit and, therefore, there is an accumulation of reactive oxygen species and consequently oxidative stress [6,9–17].

Nowadays, oral and intravenous (IV) administrations are the most used in patients with depression or anxiety. However, for drugs whose target is the CNS, these routes have many disadvantages. The oral administration of central-acting drugs results in a low drug uptake by the brain and high drug distribution in the peripheral tissues. One of the main reasons for the failure of antidepressants and anxiolytics is the presence of the blood– brain barrier (BBB) and the existence of efflux pumps in the brain capillaries, endothelial cells, luminal membranes, and caveolae. As most antidepressant and anxiolytic drugs are substrates of these transporters, their brain bioavailability is limited, which causes a decrease in their effectiveness. Additionally, drugs that are administered orally can undergo chemical and metabolic degradation in the gastrointestinal tract, have drug–drug or food– drug interactions, have a slower therapeutic action which makes them non-adequate for emergency situations, and are only suitable for patients with the ability to swallow. On the other hand, the IV route is best in cases of emergency or when the patient is unable to swallow. However, it also has many disadvantages, such as invasiveness and the need for patient hospitalization, and difficulties in delivering the drug to the CNS due to the lack of penetration of the BBB [12,14,18–21].

The BBB is a physical and metabolic barrier that limits the transport of substances between the blood and the neuronal tissue and is responsible for maintaining the physiological stability of the brain and protecting the CNS from toxic agents and microorganisms. It is made of three layers, but it is the innermost layer that poses a greater problem for drug delivery to the CNS. The BBB is essentially made up of endothelial cells in the capillary walls and tight junctions that prevent the transport of drugs through the paracellular pathway between adjacent endothelial cells in the inner layer. The BBB also has a biochemical layer with high levels of efflux transport proteins, such as P-glycoprotein (P-gp) and multidrug-resistant protein-1, as well as the expression of many metabolic enzymes, which limit brain-drug uptake [22,23]. Despite all these limitations, small (molecular weight below 500 Da) and hydrophobic molecules, and some cells (such as monocytes, macrophages, and neutrophils) can be selectively transported to the brain [21–25].

Additionally, although currently a lot of different treatment strategies exist, including pharmacological treatments, psychotherapies, and brain stimulation techniques, less than half of patients achieve a complete remission with the first treatment [17,26,27]. For these reasons, several solutions have been studied to fight depression and anxiety in a more effective and safe way.
