What does the pharmacological approach to anxiety looks like? - Chapter 4

Fear is a learned emotional and physiological response to events in the environment. It affects behavior, heart rate, hormone release and physical sensations. Through these experiences people learn to avoid dangerous situations. Before there is fear, signals first have to be sent to the brain. This goes with the help of the amygdala nuclei that are located in the temporal lobes. In this area, sensory information from a threat will be sent. The rest of the information from this threat, is sent via the amygdala to other parts of the brain, such as the hypothalamus, punch and medulla. The amygdala is the most important brain structure that has to do with anxiety. Without the amygdala, there are almost no emotional reactions. In addition, the hypothalamus controls the release of hormones and the punch and medulla provide responses to anxiety such as stiffening, heartbeat and facial expression.

Two other areas in the prefrontal cortex are also very important in anxiety. These are the ventromedial prefrontal cortex and the orbitofrontal cortex. These areas ensure that the context of the situation gets an emotional charge and thus lead to the behavior of the person. They receive information from the amygdala, thalamus and ventral tegmentum. Subsequently they send information back to the hypothalamus and cingulate cortex and they also send stop signals back to the amygdala. The cingulate cortex receives input about the state of the body and connects an emotion to it. An example are physiological reactions (heartbeat, breathing, facial expressions etc.) and behavior, these different stimuli are taken together under the emotion anxiety. As soon as the emotion can be ignored, stop signals are sent to the amygdala and there are no physical reactions to the emotion anymore. This is all part of a direct fear response. People can also worry for a longer time. This is another form of anxiety in which there are no emotional stimuli to cause the fear response, but where thoughts alone trigger enough. Fear because of worry can lead to various anxiety disorders that will be discussed further in this summary.

When does someone has a panic disorder?

The person suffers from repeated unexpected panic attacks and is afraid of another attack or the consequences of such an attack for at least one month. Often the greatest fear is the fear of dying during an attack. During a panic attack there must be extreme anxiety and at least four of the following symptoms occur: palpitations/accelerated heartbeat, sweating, shaking or stiffening, shortness of breath, suffocation, chest pain, nausea, dizziness/fainting, depersonalization, anxiety for loss of control, fear of death, paraesthesia (numb/tingling) and shivers/heat shakes. A panic disorder can also lead to agoraphobia, in which a person no longer dares to go outside because of fear of a subsequent panic attack in a place where he/she cannot escape from the situation.

What are the criteria for a generalized anxiety disorder?

GAS usually occurs in adolescence or young adulthood, but it can also occur in children. Sometimes GAS seems to disappear for a number of years and suddenly reappears in periods of stress.

The criteria for GAS are:

• Extreme fear and worry for several days to six months;
• Difficulty in keeping worrying in control;
• The anxiety and worries are accompanied by restlessness, fatigue, difficulty with concentration, irritation, tension in the muscles and sleep disturbances;
• It causes problems in social and daily functioning.

GAS is not hereditary or bound to genes, but strong associations have been found between GAS and depression. GAS can also occur comorbid with other anxiety disorders such as social phobias, PTSD and panic disorder.

The problem with GAS is that there are errors in the GABA receptors, which can be repaired by treating with GABA agonists. A well-known study of this is the elevated maze. Mice with different medications are placed in a maze. This maze has the shape of a + where two ends are surrounded by fences and two ends are open (where the mouse can fall off). Then there will be measured for how long the mouse stays in the closed section and for how long it stays in the open area. This has shown that mice with anxiety reducing drugs go to the open spaces quicker. By injecting GABA antagonists directly into the hypothalamus, it has been found that GABA activity in the amygdala and anxiety are regulated by the hypothalamus. With the help of this maze, a number of anxiety-reducing (anxiogenic) and fear-reducing (anxiolytic) drugs have been developed. Dopamine plays an important role in regulating stress and anxiety. In acute stress, dopamine levels in different brain areas are increased. Animals treated with dopamine antagonists appear to be protected from manipulations that would normally cause an anxiety reaction. Serotonin and norepinephrine also play a role in anxiety. Exactly what this role is, is not yet known. However, an anxiety disorder is often treated with SSRIs. In short, GABA, dopamine and serotonin dysfunctions play a role in anxiety disorders.

What medications can be used to treat anxiety?

As discussed above, we know that GABA agonists work well to reduce anxiety. Two large groups of drugs preceded this.   

Barbiturates

Barbiturates were developed in 1903 and were used until 1960 as anti-anxiety and narcotic medicaments. There are many types and names on the market. Barbiturates provide for the suppression of the central nervous system. With the discovery of this, the century of psychopharmacology began. Previously, only opium or alcohol were used to sedate. All barbiturates have the same core, but due to added molecules they vary in half-life. Those who work quickly and also from which the effects quickly disappear, are highly fat soluble and the others are low fat soluble.

The better they can be solved in fat, the faster they can reach the brain. Barbiturates were used as fear medicines for the discovery of better medicines. In addition, they stun and are (still) used for narcosis. Barbiturates can have the same effects as alcohol. They disrupt REM sleep and can only be used to a limited extent for sleep problems. If barbiturates are used interchangeably, this can lead to death. The barbiturate Amytal was formerly used as a truth serum to expose suspects, here also comes the Amytal interview. Barbiturates bind to certain GABA-a receptors. This is an ionotropic receptor that regulates the influence of chloride ions. These GABA receptors have a special binding site for barbiturates. If the substance binds to this, the receptor causes hypopolarization of the postsynaptic membrane, so that action potentials are reduced and the substance can remain active for a longer time. Barbiturates are the only substances that can bind to GABA receptors and can open them without GABA. All the other substances need GABA. The side effects of barbiturates are very serious and can cause permanent damage or even lead to death. Tolerance quickly occurs, which also reduces effectiveness. Barbiturates during pregnancy can cause the Fetal Alcohol Syndrome. The side effects of barbiturates are very serious and can cause permanent damage or even lead to death.

Benzodiazepines

Since the arrival of the barbiturates, people knew that the symptoms of illnesses could be reduced with medicines. Around 1960, the treatment of anxiety disorders was much better with the arrival of benzodiapines. Benzodiazepines work as anti-anxiety (anxiolytix) and have hypnotic effects. The first benzodiapine was Librium, the second Valium. The benzodiazepines quickly replaced the barbiturates and became the most prescribed psychoactive drugs in the world.

Every benzodiapine has the same three-ring molecule. Additions to these rings provide the different types of benzodiazepines. There are also large differences between the half-life value and fat solubility in the benzodiazepines. The long-acting drugs are often prescribed for anxiety disorders and the short-acting drugs are used for anesthesia and narcosis.

Benzodiazepines bind to the same GABA-a receptor as the barbiturates. GABA is very important for benzodiazepines, which they need to work. As a result, there is almost no lethal overdose in benzodiazepines. There may be other side effects such as dry mouth, cognitive impairment, poor speech and reduced motor skills. These side effects can also be seen in barbiturates and alcohol. The benzodiapine Rohypnol has been temporarily abused as a rape drug in the United States, because in combination with alcohol euphoria, numbness and memory loss occur. If benzodiapines are used for sleeping problems, it may happen that the person becomes dependent on the medication to be able to sleep.

Which drugs fall under the third generation of fear inhibitors?

This is a group of medicines that have been specially developed as anti-anxiety medication. In doing so, there must be taken care to minimize the side effects and to tackle the problem as good as possible.

Patiral GABA agonists

This is a group of medicines that also work with the GABA-a receptor. They have the same effects as barbiturates and benzodiapines, but without the dangerous side effects. Few of these drugs came onto the market due to the arrival of the SSRIs.

Serotonin 5-HT1a agonists

A while later, it was discovered that serotonin receptors influence anxiety. This was due to studies with the knock-out mice in which mice without the 5-HT1a receptors were extremely afraid. This substance is therefore necessary to reduce anxiety. Although there are several 5-HT1a antagonists, all buspirone are approved for use in an anxiety disorder.

Buspirone (BuSpar)

Buspirone is a substance that ensures that substances bind to the 5-HT1a receptors. It increases serotonin synthesis and release. Just as with many antidepressants, this will take 2 to 3 weeks before you begin to notice the effect. Therefore, this is not a good way to use in acute anxiety disorder. Buspirone has fewer adverse effects than benzodiazepines and does not create dependence or addiction.

Gamma Hydroxybutyric Acid receptor agnostics (GHB)

GHB was used around the 60s of the last century, but is only mentioned because the GHB receptor is recently discovered in the brain. GHB is odorless and colorless and therefore difficult to detect. It is a vegetable substance that has the same metabolic activity as GABA.

What alternatives to drug treatment are there?

Plant products have long been mentioned as a cure for anxiety disorders. Only two herbs have found mild scientific evidence, Valerian and Inositol. Hippocrates used all the herbs of the Valerian. Research has shown that Valerian works better than a placebo in anxiety disorders. So there is slightly evidence that the herbs work on the GABA-a receptor. Inositol is a glucose and acts as a second messenger. It can be produced by the body from different types of food. Few studies have shown that inositol works better than a placebo.

When does someone have an Obsessive Compulsive Disorder (OCD)?

This is an anxiety disorder with unwanted thoughts and repeated behaviors. Not carrying out certain behaviors (compulsions) causes a lot of stress. Patients with OCD often recognize that their obsessions and compulsions are unreasonable, but that does not reduce their fear. OCD usually develops in adolescence and occurs equally in women and men. The DSM criteria for an OCD diagnosis are as follows: suffer from obsessions and compulsions and people know that they are not reasonable and they cause discomfort and hindrance in daily life. The Yale-Brown Obsessive Compulsive Scale is often used to diagnose OCD and to monitor the medication.

OCD is the only anxiety disorder with a clear neuronal abnormality. This deviation is in the circuit of the cingulate gyrus, caudate nucleus, globus pallidus and the thalamus. Hyperactivity in the caudate nucleus inhibits the globus pallidus that normally inhibits the thalamus. The increased activity in the thalamus increases the activity in the orbitofrontal cortex via the cingulate gyrus. OCD is usually treated with SSRIs or SNRIs, 50-60% of the patients respond well to this. 

What happens to someone who has PTSD?

In having the following criteria, someone can be diagnosed with PTSD: the person has experienced or seen a traumatic experience, the experience recurs in thoughts or dreams, the person avoids situations that are similar to the trauma, the person suffers from increased arousal and symptoms cause discomfort in the person's life and last at least for a month.

PTSD is an anxiety reaction that follows a trauma, during which the trauma continues to haunt you. The trauma brings stress with it and this stress can cause changes in the brain that have to do with anxiety. Research shows that in patients with PTSD the hippocampus and prefrontal cortex are smaller and there are more dendrites in the amygdala, making them more sensitive. A recent study also found that patients with PTSD have a reduced GABA inhibition.