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. It 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][2][3][4][5][6][7]}[1,2,3,4,5,6,7].

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][10][11][12][13][14][15][16][17]}[6,9,10,11,12,13,14,15,16,17].

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][19][20][21]}[12,14,18,19,20,21].

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][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][22][23][24][25]}[21,22,23,24,25].

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][17,26,27]. For these reasons, several solutions have been studied to fight depression and anxiety in a more effective and safe way.

2. Potential Strategies for Enhancing Brain Drug Targeting and Bioavailability

2.1. Intranasal Administration

The nasal cavity has three main regions: the vestibular, respiratory, and olfactory regions. The vestibular region measures approximately 0.6 cm² and is located directly at the entrance of the nostrils. It contains nasal hairs (responsible for filtering inhaled particles), squamous epithelial cells, and some ciliated cells ^{[28][29][30][31]}[28,29,30,31]. Next to it is the respiratory region (Figure 1), which corresponds to the largest nasal area, at 150 cm^{2 [21][28]}[21,28]. It is the most vascularized region with the greatest variety of cells, containing goblet, ciliated, non-ciliated, and basal cells ^[28][31][32][28,31,32]. Goblet cells are responsible for secreting mucin, water, salts, a small group of proteins and lipids, and, together with some nasal glands, form the mucus layer. The mucus forms a layer in the respiratory epithelium and can trap inhaled molecules and send them to the pharynx, where they pass through to the gastrointestinal tract ^[21][28][29][21,28,29]. Basal cells are the key cells of the nasal cavity and have the ability to differentiate into another type of epithelial cell, if necessary. These cells also help to attach the ciliated and goblet cells to the lamina propria ^[21][29][21,29]. Ciliated cells, as the name suggests, have cilia that increase their surface area. They help to move the mucus toward the nasopharynx, resulting in mucociliary clearance ^[21][32][21,32]. Together with a high degree of vascularization, this makes the nasal respiratory region a site of high drug transport into the systemic circulation. However, the respiratory region is also innervated by the maxillary and ophthalmic branches of the trigeminal nerve (V1, V2), which originate in the brainstem fossa and have been suggested as a possible target for drug transport to the CNS ^[28][30][28,30]. In turn, the olfactory region is made up of olfactory receptors, the olfactory epithelium, and lamina propria (Figure 2). Olfactory receptors are unmyelinated neurons located in the nasal epithelium. In the lamina propria, each olfactory receptor forms thick bundles of axons that become olfactory nerves and innervate the cribriform plate, forming synaptic connections with the glomeruli of mitral cells in the olfactory bulb. There are two types of basal cells in this region: horizontal basal cells and spherical basal cells. In addition to horizontal basal cells, multipotent progenitor cells, and globular basal cells, this region also contains structural support cells that encase the olfactory receptors in the olfactory region, maintaining the structural integrity and ionization of the olfactory receptors. Drugs with small sizes can be transported through the axons, by the olfactory bulb, to the olfactory cortex, reaching the cerebellum ^[21][32][33][21,32,33]. Nasal secretions are composed of approximately 95% water, 2% mucin, 1% salts, 1% other proteins (albumin, immunoglobulins, lysozymes, and lactoferrin), and <1% lipids. They move through the nose at a rate of approximately 5 to 6 mm/min, resulting in particles being cleared from the nose every 15 to 20 min. In addition, enzymes such as isoforms of the cytochrome P450 (CYP1A, CYP2A, and CYP2E), carboxylesterases, and glutathione S-transferases can also be found in the nasal cavity Therefore, the residence time of the formulation (and, consequently, the drug) in the nasal cavity will also be affected by these enzymes’ metabolism. To prolong the residence time of the formulation in the nasal cavity, and consequently increase the amount of drug that will be absorbed, biologically adhesive (mucoadhesive) excipients such as gelatin, chitosan, carbopol, and cellulose derivatives can be used ^[28][34][28,34]. IV drug delivery to the brain is largely influenced by the drug’s plasma half-life, the extent of the metabolism, the degree of non-specific binding to plasma proteins, and the permeability of the compound across the BBB and into the peripheral tissues. Due to these issues, intranasal (IN) administration has been presented as a promising alternative to the IV route, having gained increasing interest over the past few years. After IN administration, the drug can take three different routes to the brain: one intracellular route and two extracellular routes (Figure 2 and Figure 3). The intracellular route is activated after drug endocytosis by the olfactory sensory cells, and the drug is consequently transported through the neuronal axon to the synaptic clefts in the olfactory bulb, where it is released through exocytosis. Drugs are delivered by endocytosis to the olfactory sensory neurons and peripheral trigeminal neurons, and then transported intracellularly from the olfactory sensory nerve to the olfactory bulb, and from the trigeminal nerve to the brainstem. This is an extremely slow pathway and it can take hours for the drug to reach the olfactory bulb ^{[28][33][35][36]}[28,33,35,36]. In the extracellular mechanism (Figure 3), the drug can follow two different routes: it can cross the gaps between the olfactory neurons and then be transported to the olfactory bulb, or it can be transported along the trigeminal nerve to avoid the BBB. Once the drug has reached the olfactory bulb or the trigeminal region, it can be transported to other areas of the brain by diffusion, which is facilitated by a perivascular pump that is activated by arterial pulsation ^[28][32][35][28,32,35].