13 Anxiety Disorders

This lecture opens the course’s section on mental health. It has three learning objectives:

1. Understand the context of mental health treatment history.
2. Describe the neural basis of anxiety and stress disorders.
3. Describe how pharmaceuticals treat these disorders.

Mental health disorders: considerations

Two further points frame the topic:

• We don’t know much yet, but we’re working on it.
• While conditions are always improving, mental health is still stigmatized, and as a result many disorders are underrepresented and undertreated in populations.

The slide’s picture is a word cloud of the names of mental disorders (depression, anxiety, PTSD, schizophrenia, bipolar disorder, ADHD, OCD, many phobias and more) in the shape of a human head.

Mental health: a history

Ancient civilizations

Ancient civilizations described and treated mental health disorders.

• Their accounts were based in religious belief: disorders were the “hands” of deities (the Hand of Ishtar, a Mesopotamian goddess, for example).
• Hallucinations were ascribed spiritual meanings.
• The ancient Greeks first described “melancholy”, “hysteria” and “phobia”.
• Treatments were largely developed in Persia, Arabia and the Islamic empire.

The slide shows two illustrations from medieval Arabic manuscripts: a physician offering a medicinal plant to a patient, and a man preparing a remedy under trees, beside a hanging vessel.

The Middle Ages to the 19th century

• In the Middle Ages, mental illness was put down to the “Devil’s influence”, demonic possession and witchcraft. Through the 17th century, mental illness was viewed as a disconnect from the soul and morality, which led to exceptionally poor treatment of patients.
• The 19th century was the era of “insane asylums”. Diagnoses and treatments were being widely developed, but with little standardization. The term “psychiatry” was first coined.

The slide shows an 18th-century engraving of an asylum ward: a half-naked patient being chained on the floor, other inmates around the room, and two fashionably dressed women visiting.

The 20th century

The 20th century brought psychoanalysis, and with it several changes:

• asylums were renamed “hospitals”;
• inmates were renamed “patients”;
• clinical psychology was officially recognized as a profession, driven by World War I, which left many “shell-shocked” veterans.

The first Diagnostic and Statistical Manual of Mental Disorders (DSM) was developed around World War II. The term “stress” was first applied to mental disorders after its first endocrinological description (endocrinology is the study of hormones) in the 1930s. The slide’s photo shows wounded World War I soldiers being bandaged in a trench.

Many new therapies were developed in this period, though with many flaws:

• electroconvulsive therapy (passing an electric current through the brain to set off a seizure);
• insulin shock therapy (putting patients into comas with large doses of insulin);
• lobotomies (surgically cutting the connections of the prefrontal cortex);
• chlorpromazine (an early antipsychotic drug).

The photo shows nurses and a doctor holding a patient down on a bed during a treatment.

Moral and semantic debates about the concept of mental illness arose in the 1960s:

• some argued that mental illness was a myth;
• some saw it as a label applied to conformists and non-conformists in societies;
• the APA’s (American Psychiatric Association’s) listing of homosexuality as a mental disorder drew large criticism.

From the 1970s on

In the 1970s, psychiatric hospitals began to close in favor of community services and true medical services. There was a pharmacological boom:

• “psychic energizers” (antidepressants);
• lithium;
• benzodiazepines.

In the 1990s and 2000s, new therapies and pharmaceuticals were developed:

• cognitive-behavioral therapy;
• a growing emphasis on individualized treatment;
• ongoing reclassification of disorders in the DSM.

The slide shows a pill bottle with tablets spilled around it.

Anxiety and stress disorders: overview

Anxiety and stress disorders are characterized by significant feelings of anxiety and fear.

These disorders can present as the physical symptoms of the fight-or-flight response. They are among the most prevalent psychiatric conditions in the USA; the lecture ranks them second, after substance use disorder.

The slide shows Edvard Munch’s painting The Scream.

The HPA axis

The HPA axis releases stress hormones in the body. Its main one is cortisol; the lecture also lists adrenaline, which the adrenal glands release as well, although adrenaline release is driven mainly by the sympathetic nervous system rather than by ACTH.

The HPA axis works very much like the HPG axis that regulates testosterone and estrogen. Like the HPG axis, it regulates itself by negative feedback: cortisol acts back on the hypothalamus and pituitary to reduce its own release.

Some dysregulation of the HPA axis is found across a wide range of mental health disorders.

Neural correlates of anxiety disorders

Endocrine mechanisms

Anxiety disorders involve dysregulated HPA-axis function. The majority of anxiety disorders have an overactive HPA axis:

• increased cortisol and other stress hormones;
• generally thought to come from impaired negative feedback on CRH release.

HPA-axis overactivation also inhibits the HPG axis, so high stress hormones decrease testosterone and estrogen. Bearing in mind the roles of those hormones in cognition, behavior, function and development, you can see where some symptoms of anxiety disorders start to appear.

HPA-axis overactivation and the brain

Overactivation of the HPA axis causes neurotoxicity (damage to neurons) in the:

• prefrontal cortex (PFC);
• hippocampus;
• amygdala.

It also impairs how these brain regions communicate. The slide’s diagram of a head in side view labels the three regions: the prefrontal cortex at the front of the brain, and the amygdala and hippocampus deep inside it.

Major neuroanatomy of anxiety

Anxiety involves dysregulation in two pathways: PFC → amygdala and hippocampus → amygdala.

Typically, the prefrontal cortex and the hippocampus send inhibitory GABA signals to the amygdala. In anxiety, the GABA that reaches the amygdala from the PFC and hippocampus is impaired.

GABA is the “off switch” neurotransmitter: it is inhibitory. Low GABA in the amygdala amounts to a missing off switch, so the amygdala keeps firing inappropriately, which can cause a strong fear or anxiety response. These particular circuits seem to be the ones dysregulated in anxiety disorders, and the same thing appears again in depression. Think about what the circuits may be doing, given the functions of the PFC and the hippocampus, and how that gives rise to anxiety symptoms.

Three memory checks followed (see Check yourself).

Pharmaceuticals

On drugs for mental health disorders, the lecturer’s verdict: “There’s the ones that work badly, and the ones that work worse.”

Pharmaceutical treatments for anxiety disorders

• Selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) act on serotonin and/or norepinephrine. They are the front-line treatment.
• Benzodiazepines (GABA agonists) are second-line treatments. They are not preferred because of their risk of abuse.
• There are no medications that can treat CRH dysregulation.

How SSRIs and SNRIs work

1. Serotonin or norepinephrine is released into the synapse.
2. Normally, leftover neurotransmitter is re-absorbed into the sending neuron during reuptake (through the transporters in its membrane, the last step of synaptic transmission).
3. These drugs act as reuptake antagonists: they block reuptake.
4. So the neurotransmitter remains in the synapse.

The slide’s diagram shows a pre-synaptic nerve ending releasing serotonin (5-HT) from its vesicles into the synapse, where it reaches the receptor sites on the post-synaptic nerve ending; an SSRI blocks the reabsorption of serotonin into the pre-synaptic ending.

Benzodiazepines

Common benzodiazepines include Xanax and Valium.

• They increase the effectiveness of GABA, decreasing neuron excitability: they are GABA agonists.
• They have promising short-term benefits but are not particularly effective in the long term.
• They carry a high risk of abuse, dependence and overdose.

The slide recalls the action potential to show what “decreasing excitability” means. At rest (5) the membrane sits at −70 mV. A stimulus (1) that doesn’t bring the membrane to the −55 mV threshold gives only failed initiations; one that does triggers depolarization (2), as Na ions flow in and the voltage peaks near +40 mV. Repolarization (3) follows as K ions flow out, overshooting into hyperpolarization (4) before the membrane returns to its resting state (5). GABA moves a neuron away from threshold (it lets Cl into the cell, making the inside more negative), so by boosting GABA, benzodiazepines make neurons less likely to fire.

The lecture then posed a puzzle about norepinephrine and SNRIs, and closed with two more memory checks and an exit discussion (see Check yourself).

Check yourself