Anxiety Disorders - The Use Of Neurosteroids As Neuromodulators
According to recent epidemiological research, they are the most common type of mental problem, with a high degree of comorbidity with other physical and psychiatric conditions.
DSM-IV-R currently recognizes six primary anxiety disorders: panic disorder (characterized by recurrent panic attacks), generalized anxiety disorder (characterized by frequent worrying), post-traumatic stress disorder (the result of a traumatic experience), obsessive-compulsive disorder (characterized by repetitive obsessions and the urge to perform specific acts or rituals), and specific phobia (characterized by specific stimuli eliciting fear and/or anxiety).
Anxiety disorders can be effectively treated with both medication and psychotherapy. The selective serotonin reuptake inhibitors (SSRIs) are first-line medications that show anxiolytic benefits after many weeks of treatment.
Benzodiazepines (BDZs), on the other hand, are the most frequently utilized anxiolytic drugs and have a rapid onset of action. Anxiety disorders such as panic disorder have been linked to low levels of Γ-aminobutyric acid (GABA).
COPYRIGHT_OAPL: Published on https://www.oapublishinglondon.com/hh/anxiety-disorders/ by Dr. Cooney Blades on 2022-07-22T05:41:49.741Z
Anxiety is defined as a state of tension, disquiet, or worry that exists in the absence of an imminent threat. It is distinct from fear, which is the body's normal reaction to imminent danger.
Anxiety is a natural reaction to stress, and therefore it can be beneficial at times, making you more aware and ready to act.
Anxiety disorders and the typical emotions of anxiety are not the same thing. Many of us experience anxiety when confronted with stressful events, but if those feelings persist, the worry may become chronic. An anxiety disorder may be present when emotions of fear or uneasiness become severe, difficult to regulate, or interfere with daily life. We all experience anxiety from time to time, but with an anxiety disorder, the anxiety is rather constant and has a significant negative and invasive impact on quality of life.
What is an Anxiety Disorder?
Anxiety disorders have a wide range of symptoms, and no two people have the same experience. Each illness also has its own set of symptoms. The following symptoms are typical of anxiety disorders in general:
- Being unable to be calm
- Tingling or numbness in the hands or feet
- Having sweaty or cold hands and/or feet
- Irregular heartbeat
- Feeling nauseous
- Tightness of the muscle
- Feeling nervous, worry, panic, fear, and unease
- Dry mouth
- Feeling dizzy
- Finding it hard to sleep
Sweating, a racing heart, shortness of breath, shaking, worry, or tension are physical and psychological indications of fear and anxiety. These are cues that something could be a threat and that you need to deal with it.
Flight or fight awakens physical and psychological resources to deal with threats. Sometimes this mechanism goes into overdrive and does more harm than good, and this could suggest nervousness.
Anxiety disorders are classified into numerous kinds. Even though they all have anxiety symptoms, each has its own set of characteristics, signs, and diagnostic criteria.
Agoraphobia is the unreasonable and intense dread of being trapped in a situation from which there is no way out. People often worry about having panic attacks or other symptoms in public. This makes them avoid situations where they might feel scared, helpless, or trapped.
These avoidance habits are frequently life-threatening, prompting people to avoid driving, shopping in public, flying, and other situations. This fear can grow so intense in some circumstances that people are unable to leave their houses.
Generalized anxiety disorder (GAD) causes excessive worry and anxiety. This fear is hard to control and shifts regularly. People with GAD feel nervous about ordinary events, current news, relationships, or potential events.
Panic disorder causes strong, persistent panic attacks without warning. Rapid heartbeat, increased respiration, and acute fear are panic attack symptoms.
The 5 Major Anxiety Disorders
Selective mutism causes childhood worry and causes fear, embarrassment, or anxiety that keeps kids from speaking up at school or around strangers.
Selective mutism usually begins between ages 2 and 4 and is accompanied by fidgeting, lack of eye contact, and a lack of expressiveness.
Social anxiety disorder (SAD) was formerly called social phobia. This phobia may focus on specific events like public speaking or be more generic.
People with this syndrome feel constantly watched. They may be self-critical and fearful in social situations.
Shaking, rapid heartbeat, stomach distress, and fear are symptoms. These symptoms make people avoid social events.
Certain phobias involve extreme, unreasonable fear of a specific object or scenario. When people with a specific phobia face their fears, they sweat, cry, shake, have a fast heartbeat, and breathe more quickly.
People with phobias may go to tremendous measures to avoid their fear, as with other anxiety illnesses. This might generate tension and hinder everyday activities.
Depression and anxiety may be caused by serotonin deficiency in several brain areas. In the 1950s, the fact that imipramine, a tricyclic compound, and iproniazid, a drug used to treat tuberculosis, helped people with depression and anxiety led to the idea that affective disorders are caused by a lack of monoamines.
Serotonin affects mood, affect, learning, aggression, and stress response. 5-HTP is a metabolite of L-tryptophan that is transformed to serotonin by aromatic L-amino acid decarboxylase. SERT also reuptakes 5-HT from cells.
SSRIs are a major advance in psychiatric medication. SSRIs limit serotonin absorption into presynaptic nerve terminals, boosting 5-HT in the synaptic cleft and extending its action at postsynaptic receptor sites. SSRIs may desensitize presynaptic 5HT1A receptors after several weeks. 5HT1A somatodendritic autoreceptor activation reduces serotonergic axon firing and boosts neurotransmission.
Serotonin transporter knockout mice and the resulting change in 5-HT homeostasis taught, for example, that 5-HT receptor density might vary. 5-HT1A and 5-HT2A receptors are decreasing, while 5-HT1C receptors are increasing. 1A, 2A, and 2C serotonin receptor subtypes are important in mood and anxiety regulation. Long-term fluoxetine alters cannabinoid type-1 receptor activation via 5HT1A receptors.
Sigma receptors are an opioid subclass. Two distinct receptors, sigma-1 and sigma-2, have been characterized.
Sigma-1 receptors are researched in learning, memory, depression, schizophrenia, and drug misuse. They can bind exogenous ligands with distinct therapeutic and pharmacological characteristics. In the conditioned fear stress model, the sigma-1 agonist (+)-SKF-10,047 reduced anxiety. Noda et al. found that neurosteroids exacerbated this effect.
Neurosteroids are likely endogenous sigma-1 ligands. Sigma ligands can counteract neurosteroids's antidepressant and anxiolytic activity. Steroids, especially progesterone, reduce sigma receptor binding in the brain and spleen. Progesterone is a very strong antagonist for the sigma-1 receptor, while pregnenolone, DHEA, and their sulfate esters are all agonists.
Pregnenolone sulfate and DHEA sulfate attenuated the conditioned fear stress response in mice in a dose-dependent manner, similar to (+)-N-allylnormetazocine (+)-SKF-10,047. NE-100, a sigma-1 antagonist, attenuated these effects. Sigma-related behavior can be regulated by endogenous neurosteroids, specifically progesterone. Sigma-1 receptor agonists' effectiveness is inversely associated with endogenous progesterone.
Anxiety is frequently treated with Γ-aminobutyric acid or serotonergic drugs. BDZs and SSRIs are common treatments because more and more evidence shows that glutamatergic neurotransmission is linked to the stress response and anxiety disorders.
Neurosteroids alter neuronal excitability by interacting with neurotransmitter receptors. While 3α, 5α-THP binds to GABAA receptors and increases Cl-channel opening time and frequency. Pregnenolone sulfate (PREGS) is a positive NMDA receptor modulator and a negative GABAA receptor modulator. Behavioral studies demonstrate that progesterone or progesterone metabolites (such as 3α, 5α-THP) boost the anxiolytic profile in anxiety tests such as the elevated plus maze or the open field test.
3α, 5α-THP administered systemically in mice demonstrated an anxiolytic character similar to benzodiazepines or barbiturates. Neurosteroids that modulate GABAA receptors are anxiolytic, sedative, and anticonvulsive. When PREGS were administered intravenously, the effects on anxiety reactions varied according to the dose and the behavior test.
Translocator protein (18 KDa), formerly known as the peripheral or mitochondrial benzodiazepine receptor, transports cholesterol from the outer to the inner mitochondrial membrane, restricting steroidogenesis.
Cholesterol translocation synthesizes pregnenolone and ring A-reduced neurosteroids, which may increase GABA-mediated neurotransmission. Translocator protein ligands may boost neurosteroidogenesis to treat anxiety.
Translocator protein expression on platelets or lymphocytes is reduced in anxiety disorders such as GAD, GSD, panic disorder, adult separation anxiety disorder, and PTSD.
Some translocator protein ligands exert acute anxiolytic and anti-conflict activity in animal models. Serra et al. found that selective translocator protein ligands, such as 2-phenyl-imidazo [1,2-a] pyridine derivatives (CB 34, CB 50, and CB 54), increased brain concentrations of pregnenolone, progesterone, 3α, 5α-THP, and allotetrahydrodeoxycorticosterone (3α, 5α-THDOC) and had a substantial anti-conflict effect in Vogel test. Verleye et al. discovered a favorable association between etifoxine, an anxiolytic-like chemical in rodents, and human adjustment disorder with anxiety.
In intact male rat forebrain membrane, etifoxine reduced PK11195's binding uncompetitively. Adrenalectomized-castrated (ADX-CX) rats given an anxiolytic-like dose of etifoxine had higher plasma and brain concentrations of pregnenolone, progesterone, 5α-DHP, and 3α, 5α-THP than sham-operated rats.
After activating translocator protein in the brain, increased 3α, 5α-THP synthesis may contribute to etifoxine's anxiolytic-like effects. Kita and Furukawa studied the anxiolytic-like effects of AC-5216, a translocator protein ligand, in mice, and they found that AC-5216 requires freshly produced neurosteroid hormones.
An anxiety disorder may develop as a result of prolonged exposure to high levels of stress over a period of time. Someone who has a predisposition to anxiety disorders may be more likely to develop the disorder after experiencing a traumatic event. Hereditary factors have a role, as anxiety disorders frequently run in families.
Anxiety disorders are known to cause symptoms such as a racing heartbeat, palpitations, and soreness in the chest. In addition to this, there is a possibility that you will develop excessive blood pressure as well as heart disease. Anxiety disorders have been shown to increase the risk of coronary events in patients who already have heart disease.
Your worry is out of your control, and it's causing you a lot of stress. Your anxiety makes its way into all aspects of your life, including the classroom, the workplace, and your personal relationships. You are unable to let go of your worries, and you worry about a wide variety of things, including major issues like your career or health, and minor problems like doing the chores around the house.
Anxiety disorders are the most prevalent kind of mental illness, affecting roughly one in every four adults at some point in their lives. However, anxiety disorders may be treated, and there are a variety of treatments that are proven to be helpful. Most people get better after treatment, which allows them to live normal, useful lives.
Neurosteroids are potent central nervous system modulators that alter a variety of neurophysiological processes. They begin to act at low doses and may affect various neurotransmitter pathways.
Their capacity to control several pathways that interact with one another makes them promising candidates for the pharmacotherapy of anxiety disorders, especially when combined with other mental illnesses such as mood disorders.
One goal could be to find a synthetic NS with strong anxiolytic-like effects that can be easily distinguished from sedative/ataxic effects.
The new medications should have a high oral bioavailability. NS appears to be less addictive than benzodiazepines.
Reduced abuse liability, combined with a lack of interaction with ethanol, may provide an advantage over currently available benzodiazepine anxiolytics.
Furthermore, translocator protein ligands can increase steroid synthesis, restore neurosteroid-mediated neurotransmission in the brain, and so compensate for anxiety conditions.
People with anxiety disorders have been found to have lower levels of translocator protein. Using ligands to increase translocator protein steroidogenesis may be a new way to treat anxiety.