PSY3CNN Week 8 - Mood Disorders, Anxiety Disorders & Schizophrenia

Mood Disorders

Mood Disorder Types:
- DSM-5-TR identifies many types of mood disorders.
- Affect exists on a continuum from low (depression) to high (mania).
Symptoms of Mood Disorders:
- Major Depressive Disorder:
  - Depressed mood or loss of pleasure/interest.
  - Feelings of worthlessness or guilt.
  - Disruption of normal eating habits.
  - Sleep disturbances.
  - General slowing of behavior.
  - Recurrent thoughts of death.
  - Can include antenatal or postnatal depression.
- Mania:
  - Extreme excitement with excessive euphoria.
  - Grandiose plans and uncontrollable hyperactivity.
- Bipolar Disorder:
  - Alternate periods of mania and depression, sometimes with regular behavior in between.
Prevalence of Mood Disorders in Australia:
- Depression affects 1 in 7 people.
- Major depressive episodes are more common in women, emerging in adolescence.
  - Adolescence: 1 in 5 people aged 10-24.
- During pregnancy, around 10% of women experience depression, increasing to 16% in the first three months after birth.
- One in 50 Australians experience bipolar disorder each year (Meta-analysis by Kasturi et al., 2023).
Theories of Mood Disorders:
- Biological:
  - Neurotransmitter and endocrine system alterations.
  - Altered sleep patterns.
  - Genetics.
- Psychological:
  - Altered cognitions, behaviors, interpersonal relationships.
  - Impact of sociocultural environment.
- Etiology likely involves biological, psychological, and social factors.

Neurobiological Aspects of Major Depression

Neurochemical:
- Stress and hypothalamic-pituitary-adrenal axis (HPA) axis.
- Severe life stressors are risk factors for depression.
- The best-established change is oversecretion of cortisol.
- Cortisol is a hormone secreted by the adrenal glands, associated with stress reactions.
- In depression, the negative feedback loop fails, resulting in chronic activation, experienced as chronic stress.
- Image credit: Biorender. Corticotropin-releasing hormone.
Stress and HPA axis:
- The relation between cortisol and depression is complex:
  - Severity of acute depression can correlate with cortisol levels.
  - But this correlation is not seen in chronic and less severe depression.
  - Changes in how the HPA axis reacts and recovers from stressors correlate better with depression.
  - In females, HPA responsiveness to stress varies across the menstrual phase, during pregnancy and after birth, and with menopause. This variability may contribute to the greater incidence of depression in women.
  - Most current antidepressants influence cortisol levels and appear to normalize HPA axis function (but not via reduced cortisol!).
- In depression, the negative feedback loop fails, resulting in chronic activation. This is experienced as chronic stress. There is a blunted reaction and impaired recovery to a stressor. Deactivation negative feedback loop. Image credit: Biorender. Corticotropin-releasing hormone.
Monoamine and serotonin theory of depression:
- Specific monoamine receptors may be disrupted in depression: serotonin, norepinephrine (noradrenaline), dopamine.
- Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac) are often first-line treatments for depression.
  - Acutely, they increase serotonin in the cortex.
  - Long-term use may produce unintended compensatory effects opposite to acute effects.
- Major problem: Recent comprehensive reviews have failed to find convincing evidence that depression is correlated with or caused by lower concentrations (peripheral) or activity of serotonin (Moncrieff et al., 2023).
Selective Serotonin Reuptake Inhibitors (SSRIs):
- SSRIs block the serotonin transporter, preventing the reuptake of serotonin, increasing serotonin availability in the synapse.
- How effective are SSRI antidepressants?
  - Slow response rate of weeks to months.
  - Large reviews indicate small, beneficial effects of SSRIs compared to placebo on depressive symptoms (Jakobsen et al., 2020). However, the effect size is small and below thresholds for clinical significance.
- A problem for serotonin theory of depression: Lowered (not higher) serotonin concentration is associated with long-term SSRI antidepressant use (Moncrieff et al., 2023).
- Pervasive view in public of “chemical imbalance” in depression can influence decisions to take and continue medication.
- Serotonin action is terminated by reuptake into the presynaptic terminal via SERT. Serotonin is then either degraded by MAO or repackaged into synaptic vesicles. Image Credit: Adapted from ‘Serotonin Degradation’ by Casey Henley. Hedges Introduction to Neuroscience open access textbook (CC-BY-NC-SA) 4.0 International License.
Neurotrophic Theory
- Recent research suggests that SSRI and other antidepressant therapeutic actions are largely driven by brain-derived neurotrophic factor (BDNF) and binding to tropomyosin receptor kinase B (TrkB) receptors.
- Peripheral levels of BDNF in people with depression increase after antidepressant treatment.
- Animal studies indicate that lower BDNF levels result in reduced hippocampal neurogenesis and the loss of neurons and glial cells.
- SSRI antidepressants increase the release of BDNF and number of TrkB9. SSRIs stimulate hippocampal neurogenesis, restoring neural cell levels.
Novel Therapeutics - Ketamine and Psychedelics:
- A focus of current research is exploring novel therapeutic drugs that increase BDNF expression and/or release.
- Ketamine and Psychedelics both produce fast and persistent antidepressant effects in rodents.
  - Both bind to TrkB, with approximately 1000x higher affinity than other antidepressants and induce neuroplasticity.
- Ketamine has fast antidepressant effects in humans and offers hope for otherwise treatment-resistant depression.
  - Administered in specialized clinics at much smaller doses than used recreationally.
- An Australian trial demonstrated the effectiveness of a simple subcutaneous injection for severe depression and suicidality.
- Ongoing research aims to minimize side effects (e.g., sedation, dizziness, blood pressure elevation, dissociation) or develop therapeutics with fewer side effects than ketamine and psychedelics.
Postnatal Depression Drug - Zuranolone:
- In 2023, a rapid-acting oral pill was approved in the US to treat postpartum depression.
- In trials, women taking zuranolone showed clinically meaningful improvements in depressive symptoms by day 3, continuing throughout the 4-week follow-up compared to placebo.
- Marked fluctuations in reproductive hormones and individual responses may contribute to postnatal depression onset.
  - The hormone allopregnanolone (a metabolite of progesterone) peaks in the 3rd trimester and rapidly decreases after childbirth.
  - Allopregnanolone can alter functional connectivity in the brain and modulate gamma-aminobutyric acid (GABA) A receptors.
  - Zuranolone is a neuroactive steroid that modulates GABA A receptors.
Psychological Treatments
- Combined pharmacological (e.g., SSRIs) and psychological therapies can have statistically significant effects over psychological therapy alone. However, no differences are often found at long-term follow-ups (SSRIs).
- Cognitive behavioral therapy usually involves changing unhelpful thinking and behavioral patterns. May involve strategies to develop better coping skills, deal with emotions, and interact with others.
- Interpersonal psychotherapy – based on the assumption that depression and interpersonal problems are interrelated (social functioning and relationships).
- Self-help and lifestyle changes – Sleep hygiene, Exercise ( $BDNF$ !), Ability to participate in everyday activities and return to work are important outcomes for patients.

Neurobiological Aspects of Bipolar Disorder

The exact cause of bipolar disorder is not fully understood yet.
It is frequently inherited.
- Genetic factors may account for roughly 80% of the condition’s cause.
- Parent with bipolar – 10% chance in child.
Onset is often associated with stressful life events.
Mood stabilizers (e.g., lithium carbonate) help with mania.
SSRIs are commonly used for depressive symptoms.
Antipsychotics are used for psychotic symptoms.
Psychological therapies are important co-therapies.
Summary: Mood Disorders
- Mood disorders are common.
- SSRIs have been widely used as a pharmacological treatment for depressive symptoms. Antidepressant actions were first thought to relate to serotonin.
- New evidence suggests BDNF-TrkB signaling underpins therapeutic actions of several types of antidepressants.
- Postnatal depression may relate to hormonal fluctuations in allopregnanolone. New treatments can restore GABAergic inhibition.
- Psychological therapies can be effective for mood disorders by changing unhelpful thinking and behavioral patterns and building social skills.
- Bipolar Disorder is a complex condition, with a strong genetic component, and can be managed with combined pharmacological and psychological therapies.

Anxiety Disorders and Posttraumatic Stress Disorder (PTSD)

Image Credit: Lynch, Jaffe, Fvasconcellos, Whidou, 2020, Brain structures involved in dealing with PTSD, Wikimedia Commons, CC BY-SA 4.0.
Anxiety Disorder Types and Symptoms
- Panic Disorder
  - Recurrent attacks of intense terror that arise without relation to external circumstances.
- Generalized Anxiety Disorder
  - A sustained state of worry, with at least three of restlessness, decreased energy, difficulty concentrating, muscle tension, irritability, and sleep disturbance.
- Obsessive-Compulsive Disorder
  - Compulsive repeated acts (e.g., hand washing) and repetitive, intrusive thoughts (obsessions).
- Specific Phobias
  - Fear of a specific object (e.g., dog, spider) or situation (e.g., public places, social situations).
Posttraumatic Stress Disorder (PTSD) Symptoms
- In DSM-5-TR, PTSD is now considered a Trauma- and Stressor-Related Disorder, rather than an anxiety disorder.
  - Requires exposure to one or more traumatic or stressful events
  - Intrusive memories and/or dreams, persistent avoidance of stimuli associated with the traumatic event, negative alterations in cognitions and mood, and increased physiological arousal and reactivity associated with the event.
Prevalence of Anxiety Disorders in Australia
- The most common mental illness - affects 1 in 4 people in Australia.
- Often emerges in adolescence
  - 3 in 10 people aged between 10 and 24 in Australia.
- High comorbidity with depression.
- Many people affected by anxiety do not get treatment.
Theories of Anxiety Disorders and PTSD
- Stressful or traumatic life events are a strong risk factor for anxiety. Both recent and early life adversity are associated with anxiety.
- A common symptom is excessive fear and anxiety.
- Research on fear provides insight into why excessive fear develops and how to reduce fear with behavioral and pharmacological therapies.
Neural Networks of Fear
- Amygdala-driven fear and anxiety are regulated through bidirectional connections to the ventromedial prefrontal cortex (vmPFC) and the anterior cingulate cortex (ACC). The hippocampus communicates with these regions, particularly for contextual control (i.e., is fear appropriate in this environment?).
- This model translates across species and fits with observations in patients with anxiety and PTSD.
- As Craske et al. (2017) note, “differences in the degree and coordination of amygdala, vmPFC and hippocampus activity correlate with how well mice, rats or humans can suppress anxiety, extinguish fear and avoid cognitive bias to potential threat.”17
- PTSD involves amygdala hyperactivation with reduced vmPFC activity to cues signaling threat. It can be normalized with exposure therapy.
Pharmacological Treatments
- Combined pharmacological (e.g., SSRIs) and psychological therapies are most efficacious.
- Anxiolytics have some efficacy (GAD, social anxiety disorder)
  - Examples include benzodiazepines (e.g., diazepam)
  - Can act on GABA or glutamate receptors
  - Reduce anxiety but do not target learning during exposure (why they are ineffective for PTSD and phobias)
- SSRI antidepressants have good evidence of effectiveness (except for phobias) and enable joint treatment where anxiety occurs with depression.
Exposure-Based Therapies
- People with phobias go to great lengths to avoid the events that trigger their fear, despite negative consequences.
  - E.g., people with blood-injection-injury phobia can refuse routine medical care.
- Help people gradually confront their fears without avoiding them.
  - Handling nonvenomous spiders (spider phobia).
  - Entering an enclosed space (claustrophobia).
- Can be in person or virtual-reality exposure therapy for PTSD (see reading).
- However, relapse can occur over time or in different environments.
Exposure-Based Therapies
- Exposure therapies leverage knowledge from studies on Pavlovian fear conditioning and extinction in rodents and humans.
- Therapies are based on extinction training - a learning process that inhibits fear.
  - Extinction training occurs after fear conditioning. During extinction, repeated presentations of the conditioned stimulus will gradually reduce fear as the animal learns the stimulus no longer predicts danger.
Sex- and Gender-Related Diagnostic and Treatment Issues
- Women are twice as likely to experience anxiety and PTSD than men, and their symptoms are more severe.
- There are gender differences in the emotional and cognitive processing of trauma as well as effects of reproductive hormones on fear inhibition.
- The effectiveness of extinction is modulated by fluctuations in ovarian hormones across the menstrual cycle (women) and estrous cycle (female rodents).
  - Retention of what is learnt during the extinction session
Impact of Ovarian Hormones on Fear Extinction
- Females exhibit good fear extinction retention (i.e., good long-term fear inhibition) when extinguished in the phase of the menstrual/estrous cycle with high ovarian hormone levels.
- Females exhibit poor fear extinction retention (i.e., fear returns) when extinguished during the phase of the menstrual/estrous cycle with low ovarian hormone levels.
- Oral estradiol facilitates extinction in women. Potential implications for exposure therapies for women.
Nutritional Psychiatry
- Diet has long been known to affect behavior.
- Accumulating evidence supports the idea that micronutrients are critical for healthy brain functioning.
- Moderately robust evidence supporting Mediterranean diets improve symptoms of depression; some evidence for reductions in anxiety.
- Current research is examining whether diet, prebiotics and probiotics may be used to alter the gut microbiota as a treatment approach.
Summary: Anxiety Disorders and PTSD
- Anxiety disorders are common and often comorbid with depression.
- Stressful or traumatic life events are a strong risk factor for anxiety.
- Excessive fear and anxiety are symptoms of several anxiety disorders and PTSD.
- The activity and coordination of the amygdala, vmPFC and hippocampus correlates with how well mice, rats or humans can suppress anxiety and reduce fear.
- Anxiolytics have some efficacy but do not target learning underlying exposure-based therapies and so are not effective for all anxiety disorders.
- Exposure therapies help people gradually confront their fears.
- The prevalence of anxiety disorders and the efficacy of their treatment in women may relate to hormonal fluctuations.

Schizophrenia

"It’s a pretty scary illness, but it doesn’t make the people who have it scary people."
Hannah, diagnosed with Schizophrenia at 18, talks about stigma for SANE Australia.
Schizophrenia Symptoms
- Schizophrenia is a multifaceted psychiatric disorder (typically chronic).
- Psychosis is a main symptom – when a person finds it hard to tell what is real from what isn’t.
- DSM-5 listed symptoms of schizophrenia include:
  - Delusions
    - Fixed beliefs that distort reality (e.g., persecutory, grandiose).
  - Hallucinations
    - Altered perceptions (e.g., hearing voices but can be any sensory modality).
  - Disorganized Speech
    - E.g., rapid switching topics, incoherent statements
  - Disorganized or Excessively Agitated Behavior
    - Can include unpredictable agitation and problems with goal-directed behavior that impact daily living
    - Catatonic behavior – a marked decrease in reactivity to the environment (abnormal postures, lack of verbal and motor responses, stereotyped movements).
  - Negative Symptoms
    - Blunted affect, avolition (decrease in motivated self-initiated purposeful activities), and decreased experience of pleasure (anhedonia).
  - Social withdrawal and occupational dysfunction
  - Diagnosis: at least two symptoms present for 6 months and at least 1 month of active symptoms.
Development and Prevalence in Australia
- Requisite psychotic features typically emerge between late teens and mid-30s.
- Peak onset early- to mid-20s for men, mid- to late 20s for women.
- One in a 500.
- Ten percent of people with schizophrenia commit suicide.
Theories of Schizophrenia - Biological
- Emphasize biochemical and structural abnormalities
- Explain the increased chance of illness with familial link:
  - People with a parent or sibling with the condition have a 1 in 10 chance of developing schizophrenia
  - Multigenetic risk
  - Stress or drugs can trigger first episode
- Neurodevelopmental origins
  - People with schizophrenia are more likely to have combinations of early adversity (prenatal or postnatal)
  - Maternal infection, obstetrical complications, poorer maternal nutrition
  - Premorbid cognitive symptoms and slow emergence of altered brain connectivity can be evident during adolescence
  - Early adversity may shape functional connectivity of the prefrontal cortex with other regions (e.g., striatum, amygdala)

Neurobiological Aspects of Schizophrenia

Neuropathological (structural and functional)
Neurochemical
Treatments
Structural Abnormalities in Schizophrenic Brains
- Structural MRIs demonstrate gross brain alterations:
  - Enlarged lateral and third ventricles
  - Decrease in gray-matter volume in frontal (e.g., DLPFC) and temporal lobes.
  - Reductions in white matter throughout all lobes and cerebellum, with high individual variability.
  - Indicates loss or shrinkage of cortical cells for gray and white matter.
- Growing recognition that schizophrenia is associated with higher variability in structural brain measures (particularly frontotemporal regions) than healthy controls.
  - Might reflect various schizophrenia subtypes
Structural Abnormalities in Schizophrenic Brains
- Cellular studies demonstrate abnormalities in the hippocampus and dorsolateral prefrontal cortex (DLPFC).
- The hippocampus has a disorganized orientation of pyramidal neurons.
- Dorsolateral prefrontal cortex cells have a simple dendritic organization and fewer spines. Disrupted inhibitory function.
  - Relations to working memory, using contextual information to guide goal-directed behavior (cognitive control), filtering distracting stimuli.
- Parvalbumin cells have reduced GABA synthesis  Ineffective inhibition (analogy of cox in rowing).
Dopamine Theory of Schizophrenia
- Elevated dopamine receptor binding in the frontal lobe was the first clear abnormality reported in schizophrenia.
  - No longer considered the principle neurochemical abnormality.
  - Compensatory, yet insufficient, response to lower dopamine release in the DLPFC.
- Antipsychotic drugs interfere with neurotransmission at dopamine synapses – reducing activity at the D2 receptor.
- Dopamine agonists (e.g., cocaine, amphetamine, L-dopa used for Parkinson’s Disease) that enhance dopamine action (particularly D2 stimulation) can induce psychotic symptoms mimicking paranoid schizophrenia.
- Studies in rodents suggest that DLPFC dysfunction may lead to increased dopamine synthesis and release in the ventral striatum (hyperdopaminergia) and the emergence of positive and psychomotor symptoms. Antipsychotics may normalize excess striatal dopamine transmission.
- This theory only partially explains symptoms of Schizophrenia.
Dopamine Hypothesis of Psychosis
- Unaffected motor movement pathway. However, adverse side effects of older antipsychotics could be due to blocking dopamine in dorsal striatum.
- Hyperactivation of dopamine pathway.
Dysfunctional PFC Theory of Psychosis
- DLPFC dysfunction (inhibitory PV cell function) may lead to overactivation of mesolimbic pathway and hyperdopaminergia in striatum.
- Ketamine’s dissociative effects and hallucinations thought to be due to effects on prefrontal PV neurons.
Antipsychotics
- First-generation antipsychotics (e.g., haloperidol) almost exclusively block D2 dopamine receptors. They effectively alleviate positive symptoms such as delusions, hallucinations, anxiety and agitation, incoherent speech, disruptive behavior, and mania.
  - Can take months for full benefits.
  - Lower risk of suicide and severe health problems than no use.
- "Newer" (since 1990s) atypical antipsychotics were a big step forward for pharmacotherapy of schizophrenia: effective for both positive and negative (affective) symptoms and had fewer motor side effects (trembling, muscle stiffening, uncontrolled movements).
  - Multi-action e.g., block serotonin-2A comparable to or even higher than their D2 blocking potential. May explain effects on mood.
  - Do not target glutamate or GABAergic signaling, possibly accounting for their limited effects on cognitive symptoms.
Theories of Schizophrenia - Psychological
- Cognitive symptoms are the most debilitating for quality of life.
- Cognitive deficits in diverse domains – IQ, working and episodic memory, learning, language, executive function, attention, and inhibition.
  - Could be grouped together as inability to actively represent goal information in working memory needed to guide behavior (proactive control)
  - Other theories propose that the specific dopamine circuits of reinforcement learning are altered.
- Negative symptom pathology may relate to impairments in emotional experiences and anticipatory pleasure (but intact experience of pleasure in the moment).
- Cognitive and affective symptoms (emotion processing) can lead to social withdrawal and unemployment
  - can be intervention targets with CBT.
Where Cognitive Dysfunction Could “Sit” in Schizophrenia Implies Different Therapies
- Psychological mechanism (proactive control) implies cognitive behavioral therapy.
- Neurobiological mechanism (biological abnormality) implies pharmacological intervention
Summary: Schizophrenia
- Schizophrenia is a complex, heterogenous disorder in terms of symptoms and biological underpinnings.
- Increased risk with illness in family and adversity.
- Imaging and cellular studies demonstrate abnormalities in the dorsolateral prefrontal cortex (e.g., reduced GABA synthesis) and hippocampus.
- Hypodopaminergia in DLPFC but hyperdopaminergia in ventral striatum.
- Antipsychotics target the dopamine D2 receptors. They are effective for controlling positive symptoms. Newer antipsychotics are more effective for negative symptoms but still not for cognitive symptoms.
- Psychological therapies may target a core psychological deficit – proactive control.
Lecture Summary
- Mood and anxiety disorders are common and often comorbid conditions.
- Schizophrenia is less common but shares some symptoms overlapping with those disorders.
- Early life adversity is a common risk factor.
- Prefrontal cortex dysfunction is also common amongst all disorders.
- Pharmacological therapies for mood disorders, anxiety disorders and schizophrenia are assumed to target biological mechanisms directly underpinning cognitive, emotional, and behavioral symptoms.
- Cognitive behavioral therapy is used as a psychological therapy for mood and anxiety disorders as well as schizophrenia and is often most effective as adjunctive to pharmacotherapy.
Learning Objectives
- Can you: 1. Describe the major types of mood disorders, symptoms, neurobiological aspects, and current treatments? 2. Describe the major types of anxiety disorders, symptoms, neurobiological aspects, and current treatments? 3. Describe the major symptoms of schizophrenia, neurobiological aspects, and current treatments?