Mood Disorders: Depression, Anxiety, and OCD

Mood Disorders

PSYC 304, 05/01

Outline

This lecture covers the following topics:

• Depression
• Anxiety Disorders
  • Anxiety
  • OCD
• Treatments for Anxiety Disorders

The Papez Circuit

The Papez circuit is crucial for emotion generation and regulation:

• Thalamus: Begins emotion generation by combining exteroceptive and interoceptive inputs.
• Hypothalamus: Coordinates bodily and physiological responses to maintain homeostasis (appetitive, agonistic, reproduction).
• Amygdala: Crucial for fear and associative learning.
• Insular Cortex (Insula): Important for cognitive appraisal, combining extero- and interoceptive information with subjective feelings.
• OFC (vmPFC): Assigns valence to stimuli and performs "if/then" simulations based on past experience.
• ACC (dlPFC): Drives response vigor, assigns conceptual meaning, and evaluates effort.

Malfunctions within these regions or their connections can lead to mood disorders like depression and anxiety. Many symptoms of mood disorders involve changes to appetitive and agonistic behaviors governed by the hypothalamus. These symptoms can be caused by hypoactivity of amygdala inputs to the hypothalamus or disturbances to the cortical regions (ACC, OFC, Insula) that regulate the activity of the hypothalamus and amygdala.

The DSM-V

Psychologists use the Diagnostic & Statistical Manual of Mental Disorders (DSM) to diagnose mental disorders. These disorders are different from the normal feelings of sadness, fear, and worry in the duration of symptoms. The DSM defines depression as disturbances in the body and thinking that persist most of the day, every day, for at least two weeks.

Serotonin & Depression

Depression is associated with a persistently low mood and anhedonia (i.e., not enjoying things you used to like) and affects many other facets of brain function, like cognition. While the causes of depression are complex and not fully understood, it has been linked to a lack of serotonin. This could be caused by:

• Less 5-HT synthesis
• Too much breakdown of 5-HT (by the same monoamine oxidase (MAO) enzyme that breaks down the catecholamines DA & NE)
• Too much reuptake of 5-HT by SERT

Some treatments for depression, like Prozac, are selective serotonin reuptake inhibitors that prevent the reuptake of 5-HT by SERT.

Norepinephrine & Depression

One of the first treatments for depression was accidental. Isolated patients with TB were given the drug ipronizad to increase respiratory function, which it does by acting as a monoamine oxidase inhibitor (MAOi), elevating levels of norepinephrine. These patients were described as euphoric, in a constant “party mood,” despite the terrible circumstances of living in a hospital with an incurable, fatal disease. However, ipronizad was found to have toxic effects on the liver and was discontinued. However, it suggested that increased levels of norepinephrine might be able to relieve some symptoms of depression.

Inspired by ipronizad, researchers continued to study MAO inhibitors, looking to tricyclic antidepressants. Researchers found that the tricyclic antidepressant imipramine was effective at reversing depression-related symptoms in laboratory animals treated with a drug that destroys norepinephrine in synaptic vesicles. Researchers discovered that MAOi’s also increased concentrations of serotonin, leading to the development of SSRIs like Prozac, Paxil & Zoloft. These drugs elevate serotonin without impacting norepinephrine. Serotonin & norepinephrine modulate activity of regions in the prefrontal cortex.

PFC & Depression

To begin to pinpoint the specific brain regions that may contribute to depression symptoms, researchers turned to two large-scale studies that track patients with head injury. They targeted patients with injuries to either the ventromedial PFC (vmPFC, e.g., OFC) or the dorsolateral PFC (dlPFC, e.g., ACC) and assessed depression symptoms using the Beck Depression Inventory (BDI) that categorized each individual into the following groups: no/low depression, intermediate, high depression.

• People with damage to vmPFC rarely had depression.
• Very high (~80%) proportion of people with dlPFC damage had high depression scores.

They also looked at the severity of various depression-related symptoms like loss of pleasure and changes in sleep. While people with damage to vmPFC scored very low on most of them (even 0 on many). They scored even lower than controls who had no injury! People with dlPFC damage experienced a wide range of these symptoms.

The vmPFC is important for self-awareness & self-reflection (e.g., the OFC performs the "if/then" simulations based on our past experiences to help generate emotion & drive behavior); lesions to this area produce a loss of self-insight and a diminished ability to experience related negative emotions like shame, regret, and self-dislike. Thus, damage to this region may blunt depression symptoms by reducing these self-awareness and self-reflection functions. The dlPFC is important for reappraisal to ultimately produce intentions that will be converted into goal-directed actions (e.g., the ACC evaluates effort, drives an appropriate level of vigor towards a goal, and assigns conceptual meaning). Typically, this reappraisal process might serve to inhibit negative emotions & thus may be protective against depression, so damage here could then lead to depression symptoms.

Summary of Depression

• The Papez circuit—important for emotion—is implicated in many mood disorders
• In particular, these disorders are often associated with symptoms related to the behaviors governed by the hypothalamus
  • symptoms can thus be driven by differences in inputs to the hypothalamus (e.g., amygdala) or regulation of the hypothalamus and amygdala (e.g., ACC, OFC, insula)
• The DSM-V is used to diagnose mood disorders
• Depression is linked with differences in levels of norepinephrine and serotonin
• The first depression treatments (ipronizad) were coincidentally identified when treating TB patients by increasing norepinephrine by inhibiting monoamine oxidase
• Similar MAO inhibiting tricyclic antidepressants were next studied, like imipramine
• This led to the discovery that MAO inhibitors also increased serotonin levels, so SSRIs like Prozac & Zoloft came into use
• Serotonin & norepinephrine modulate activity of regions in the prefrontal cortex
• dlPFC assists in cognitive reappraisal and suppression of negative emotions and may thus be protective against depression
• vmPFC is important for self-reflection, so overactivity could lead to depression

What is Anxiety?

• Increased heart rate
• Rapid breathing (hyperventilation)
• Sweating
• Trembling
• Upset stomach or headache
• Sense of impending danger, panic, or doom

Anxiety is not fear! Fear is a response to an imminent or real threat, whereas anxiety is a feeling associated with the anticipation of potential harm in the future. Anxiety is a state of preparation for danger, which is characterized by arousal, vigilance, physiologic preparedness, and, in humans, negative subjective states qualitatively similar to fear. In the short term, feelings of fear or anxiety are normal and can even be positive.

Long-term chronic feelings of fear and anxiety can lead to negative, if not pathological, consequences.

• State Anxiety – anxiety that reflects the current situation
• Trait Anxiety – anxiety that reflects a person’s more permanent tendency

Anxiety Disorders are a class of psychological disorders that include:

Historically, PTSD has been considered an anxiety disorder. However, in the DSM-V, PTSD was moved from Anxiety Disorder to Trauma and Stressor-Related Disorders. Diagnostically, PTSD is conditionally linked to trauma, and symptoms typically arise within 3 months of experiencing a trauma. Symptoms include:

• At least one re-experiencing symptom (i.e., flashback, dream, etc.)
• At least one avoidance symptom
• At least two arousal and reactivity symptoms ( i.e., startle response, feeling on edge, etc.)
• At least two cognitive and mood symptoms (i.e., memory loss, negative feelings about one's worth, feelings of guilt, etc.)

Anxiety Disorders seem to impact women and people assigned female at birth more. Anxiety Disorders as a class also display the youngest onset of any mood or substance use disorder. Collectively, anxiety disorders are the most common mental illness in the US, affecting an estimated 40 million adults, or ~20% of the population, each year.

Neuroanatomy of Anxiety

Fear-inducing stimuli are routed through the thalamus to the amygdala, which then projects to other regions in the Papez circuit. The amygdala comprises two major nuclei, the central amygdala (CeA) and the basolateral amygdala (BLA).

The BLA receives input from multiple regions to guide the fear response, including the cortex which allows for top-down control. BLA is also crucial for associative learning (== fear memories). BLA also inhibits CeA, which is responsible for the genesis of the fear response through its downstream connections.

Overactivation or chronic activation of the CeA is associated with anxiety. Mice are prey animals and typically prefer to stay closer to the walls, especially when on high-alert (== housed in a stressful environment). Optogenetically activating the BLA->CeA circuit reduces this anxiety-like behavior. On the other hand, silencing the BLA-CeA circuit in happy mice increases anxiety-like behavior.

Another brain region—the bed nucleus of the stria terminalis (BNST)—has also been more recently linked with anxiety. People with anxiety have weaker functional connectivity between BNST and CeA, providing another potential mechanism for the dysregulation of CeA associated with anxiety disorders. BNST is part of the “extended amygdala,” which is a set of regions very similar to amygdalar nuclei in their cell types and connectivity.

Hyperactivity of the ACC has also been positively correlated with measures of trait anxiety. The insula may also play a role in anxiety, as it’s important for the anticipation of aversive events.

Summary of Anxiety

• While fear is a response to an immediate threat, anxiety is associated with an ongoing anticipation of future harm
• There are two subtypes of anxiety: state anxiety is a fleeting feeling in response to an event, while trait anxiety is more like a personality trait
• Anxiety disorders are a very common class of disorders that include OCD and GAD. In general, anxiety disorders are diagnosed more often in women compared to men
• Historically, PTSD was also classified as an anxiety disorder in the DSM
• The amygdala contains two major nuclei:
  • The basolateral amygdala (BLA) receives input from multiple regions to guide the fear response, communicating bilaterally with cortical regions to allow for top-down control and associative learning
  • The central amygdala (CeA) receives input from the BLA and projects to downstream regions that initiate the behavioral fear response
• Overactivity of the CeA is associated with anxiety in humans and animal models
• Weakened connections between BNST and CeA in people with anxiety provide one potential mechanism
• The ACC is hyperactive in anxiety, especially correlated with trait anxiety
• The insula is overactive when anticipating aversive stimuli in anxiety-prone compared to anxiety-normative people

Obsessive-Compulsive Disorder (OCD)

Obsessions are persistent, intrusive, or inappropriate thoughts that cause anxiety. Obsessive-Compulsive Disorder (OCD) is a psychological condition characterized by a pattern of recurrent obsessions and compulsions that impacts about 1-2% of the population. Compulsions are often repetitive acts (e.g. rituals) that the individual feels compelled or driven to perform. While capturing aspects of anxiety is difficult in rodents, OCD has been modeled with some validity.

Neurocircuitry of OCD

The direct pathway facilitates movement when instructed by the brain to initiate a motor plan. The indirect pathway is active at baseline to suppress unwanted movements. In neurotypical people, the constantly-active indirect pathway wins and unwanted actions are suppressed.

OCD has been linked with a hyperexcitability of the direct pathway, which drowns out the indirect pathway and makes it more difficult to ignore the compulsion to move. The OFC—which is important for assigning valence & performing the “if/then” simulations that can drive emotion—is involved in OCD. Environmental cues drive obsessive thought in the OFC, which connects with the striatum.

Summary of OCD

• Obsessive-compulsive disorder (OCD) is an anxiety disorder characterized by persistent obsessive and compulsive thoughts and behaviors
• OCD is associated with hyperactivity of the basal ganglia direct pathway
• The OFC may contribute to this overactivation

Treating Anxiety Disorders

Treatments for anxiety vary as a function of the type of anxiety and person:

• Surgical
• Pharmaceutical
• Behavioral

Surgical Treatments

Limbic leucotomy emerged as one of the earliest treatments for OCD and other anxiety disorders. Surgeons make bilateral lesions to parts of the ACC and lower medial OFC, which has been associated with a success rate of about 84%.

Pharmaceutical Treatments

Historically, anxiety has been associated with hypoactive GABA activity and consequently the hyperexcitability of the amygdala and ACC. Benzodiazepines act as GABA noncompetitive agonists, promoting the action of GABA. Diazepam (aka Valium) is a classic benzodiazepine that binds to the GABAA receptor to increase the likelihood of $Cl^-$ channel opening when GABA is released. Diazepam has a relatively long half-life (~48 hours), making it ideal for the treatment of GAD.

Barbiturates are another class of drugs that bind to a different portion of the GABAA receptor, not only increasing the likelihood of $Cl^-$ channels openings but also how long the channel is open. High doses of barbiturates can lead to respiratory depression and death, whereas overdose on benzodiazepines often induces coma but rarely leads to death (so benzodiazepines have mostly replaced the use of barbiturates for treating anxiety). There is an addictive potential to these substances.

SSRIs and newer selective norepinephrine reuptake inhibitors (SNRIs) have emerged as useful treatments for panic disorders, social anxiety, and OCD. SSRIs and SNRIs are slower-acting drugs often requiring steady use for 3-4 weeks before seeing behavioral change. It is thought that these drugs work by promoting neuroplasticity and potentially new learning that will improve a patient’s ability to respond to anxiety-inducing stimuli.

Behavioral Treatments

Exposure therapy and cognitive behavioral therapy (CBT) have been shown to be incredibly effective in treating specific phobias, as well as GAD, panic disorder, social anxiety, and OCD. Exposure therapy for specific phobias involves gradually exposing an individual to what they are fearful of. Patients show as much as a 95% improvement after a single session. Virtual reality exposure therapy (VRET) has been found to be particularly helpful, as people know they are never in danger and so can better overwrite the anticipated negative reaction.

Summary of Anxiety Treatments

• Treatments for anxiety disorders vary greatly by individual and the specific disorder
• Surgical intervention is the most invasive and typically restricted to treatment-resistant conditions
• Historically, benzodiazepines (== Diazepam aka Valium) & barbiturates were prescribed for anxiety disorders, but they both carry risks
• SSRIs and SNRIs offer safer options, but they can be slower acting and may only be effective for certain types of anxiety disorders
• Exposure therapy, both in real life & virtually (always guided by a therapist!), has emerged as one of the best methods for reducing phobias but may also be effective for other types of anxiety as well