2024 Affective Disorders: Depression and Anxiety

2024 Affective Disorders: Depression and Anxiety Journal Club

• General Points – Clinical Problem with Underlying Basic Science:
  • Introduce and discuss the clinical and neurobiological basis for psychiatric disorders.
  • Address current issues relating to diagnosis and pathophysiology, using depression as an example.

Depression (3 Lectures)

• Major Features of Depression:

  • Describe the major features of depression using clinical descriptions.

• Monoamine Hypothesis:

  • Highlight the monoamine hypothesis of depression and its empirical support.

• Antidepressant Drugs:

  • Describe classic antidepressant drugs that modulate monoamine levels.
  • Detail their molecular mechanisms of action and limitations.
  • Discuss if these drugs actually work.

• Ketamine as a Novel Antidepressant:

  • Describe the repurposing of ketamine as a novel antidepressant treatment.

Anxiety (1 Lecture)

• Pathophysiological State of Anxiety:

  • Introduce the pathophysiological state of anxiety and outline the current classification and complexity of anxiety disorders.

• Fear Pathway as a Template:

  • Highlight the fear pathway as a template to understand anxiety as a brain-based disease.

• Benzodiazepines and GABA Receptors:

  • Discuss benzodiazepines and GABA receptors in relation to anxiety, addressing how their wide expression can achieve some selectivity (anxiolytics).

• Confounds to Anti-Anxiety Medications:

  • Discuss any factors that may hinder the use of these medications.

Depression References

• Interest Reading:
  • Malignant Sadness: The Anatomy of Depression by Lewis Wolpert.
• Textbooks:
  • Pharmacology (9th Edition), Chapters 45 & 48 by Rang, Dale, Ritter, & Moore.
• Wider Perspective:
  • New approaches to psychiatric diagnostic classification (2014), M.J. Owen (Neuron 84, 555-571).
  • New approaches to antidepressant drug discovery: beyond monoamines (2006), Berton & Nestler (Nat Rev Neuroscience 7, 137-151).

Diagnosis of Psychiatric Diseases

• Categorization:

  • Diagnosis is largely based on expert categorization of presence versus absence of symptoms.

• Diagnostic Manuals:

  • Diagnostic Statistical Manual (DSM-V) and International Classification of Diseases (ICD-11).

• Pros and Cons of Current Methods:

  • Pros: Improved diagnosis.
  • Cons: Lacks pathophysiological definition. Doesn't consider symptom overlap in distinct diagnoses (comorbidities). Does not resolve specific disease causation.

• Categorization Limitations:

  • Categorization does not consider the dimensional expression or causes of psychiatric disorders and diseases.

Research Domain Criteria (RDoC) Basic Science Approach

• Domains:
  • Negative valence, positive valence, cognitive systems, systems for social processes, arousal/regulatory systems, sensorimotor systems.

Better Classification for Understanding and Treating Mental Illness

• Premise: The current system of inclusion and exclusion criteria in diagnosing mental illnesses may be flawed.
• Methods: Precision medicine to deconstruct the symptoms in mood disorders using several analytical platforms to produce homogeneous clusters of patients.
• Identified Categories: Major depressive disorder, anxiety, and bipolar depression.
• Integrated Data: Genetic risk, polygenic risk score, brain activity (insula cortex), physiology (inflammatory markers), behavioral processes (affective bias), life experience, social, cultural, and environmental factors.

Depression: Pathophysiology of Mood

• Significance: A major global health problem (6% of the world population affected; over 20% in developed countries). Significant economic burden: > $120 billion/year globally.
• Human Condition: Described as a profound and potentially devastating "grief without pang."
• Modeling Difficulties: Modeling depression in preclinical models is difficult. The best biomarker for depression is a complex behavioral trait.

Depression: Its Biological Context

• Behavioral State Changes: Mood reflects a change in a behavioral state and is strongly associated with negative thoughts.
• Evolutionary Advantage: Mood changes related to concentration and aversion have potential ties to evolutionary advantages.
• Neurological Pathways: Focus on pathways involved in concentration and mood, such as those in the prefrontal cortex and the role of serotonin.

Diagnosis of Psychiatric Disorders (e.g., Depression)

• Diagnostic Criteria:
• Persistent sadness or low mood, loss of interest or pleasure, tiredness or low energy for at least two weeks are primary symptoms.
• Associated Symptoms including disturbed sleep, poor concentration or indecisiveness, low self-confidence, poor or increased appetite, suicidal thoughts or acts, agitation and self-blame.

Biological Basis of Multiple Dysfunction in Depression

• Diagnostic Criteria:
  • Depressed Mood, Irritability, Low self-esteem, Modified appetite, Hopelessness & guilt, Weight Loss or Gain, Decreased ability to concentrate or think, Insomnia or Hypersomnia, Decreased interest in pleasurable stimuli, Recurrent thoughts of death or suicide.
• Associated Brain Regions: Limbic system (Amygdala/Hypothalamus), Amygdala, Hypothalamus, Limbic system, Hypothalamus, Hippocampus/Cortex, Superchiasmatic Nucleus and Nucleus Accumbens/Ventral Tegmental Area (VTA) and Amygdala.

What Causes Depression?

• (The provided text does not give any specific cause of this disorder).

Stress Pathway Inputs into Etiology & Treatment

• Principle Stress Pathway: Stress is a primary trigger for depression.
• Corticotrophin-Releasing Factor (CRF) and Glucocorticoids: Dysregulation of feedback inhibition elevates CRF and glucocorticoids in depressed patients.
• Glucocorticoid Effects: Elevated glucocorticoids can be neurotoxic, causing cell death and synapse loss and inhibiting neurogenesis in the hippocampus.
• CRF Receptors: CRF receptors also exist outside the hypothalamus-pituitary axis (e.g., in the amygdala).
• Change in CRF Receptor Levels: Changes in CRF receptor levels have been found in post-mortem brains of depressed patients.
• Antagonists: The importance of CRF receptor antagonists as a potential treatment option in depression is evident.

Monoamine Theory of Depression

• Neurotransmitter Levels: Elevating neurotransmitter levels available to signal improves mood.

Monoamine Theory of Depression (1960s Observations)

• Serendipitous Observations: In the 1960s, the role of monoamines (norepinephrine, serotonin, and dopamine) in depression became prominent, based on two serendipitous observations that provided evidence.
• TB Drug, Iproniazid Initially given to treat tuberculosis, this drug was observed to elevate mood in some patients.
• Antipsychotic Drug, Imipramine: Was useful in reducing mood, also suggested that elevating levels of monoamines may improve mood in this context.
• Monoamine Oxidase (MAO) Inhibitors: This group of drugs inhibits the breakdown of neurotransmitters, leading to higher levels in the synapse.
• Elevated Monoamines and Depression: Elevated levels of noradrenaline, serotonin, and dopamine are thought to alleviate depression, via blocking the re-uptake of released neurotransmitters.

Monoamine Hypothesis in a Neurobiological Context

• Monoamine Neurotransmitters: Elevated synaptic monoamines (norepinephrine, dopamine, serotonin) are associated with improvements in mood.
• MAO Inhibition: Blocking MAO (monoamine oxidase) interrupts the breakdown of monoamines, increasing their amounts in the synapse.
• Receptor Activity: This theory suggests elevated monoamines result in increased signaling to monoamine receptors.

What Happens When Monoamine Levels Rise

• Key Transmitters: Widespread increases in neurotransmitters—serotonin, dopamine, and norepinephrine—are noted across various brain regions.
• Receptor Activity: These transmitters affect various receptors including dopamine, serotonin and adrenergic and histamine receptors, resulting in a variety of downstream effects.

Modifying Potency of Sites Responsible for Transmitter Level Increase

• Tricyclic Antidepressants: Imipramine (Tofranil).
• Selective Serotonin Reuptake Inhibitors (SSRIs): Fluoxetine (Prozac).

Secondary Transporters and Uptake Inhibitors

• Co-transport: Secondary transporters in the cell membrane co-transport substrate molecules in along with Na+ and Cl- into the cell.
• Binding Sites: Substrate binds to specific binding sites within transmembrane domains.
• Inhibition by Inhibitors: Uptake inhibitors block the substrate binding site, preventing the translocation of monoamines into the cytoplasm.

Ketamine: Repurposing Drugs

• Dose-Dependent Effects of Ketamine: Different ketamine doses have varying impacts on the brain, leading to distinct behavioral states such as analgesia (anaesthesia) or a dissociative mental state.
• Anaesthesia: A 3 mg/kg dose typically produces anaesthesia and inhibits thalamic regions.
• Dissociative Symptoms: A 1mg/kg dose produces dissociative symptoms, but limits subcortical inhibition.

Comparison of Ketamine and Midazolam

• Clinical Trial: The clinical trial looked at how ketamine affected those with a baseline rating of depression, comparing it to midazolam, a sedative benzodiazepine.
• Short-term Effects: Initial improvements in symptoms were observed with ketamine.
• Long-term Effects: Hints of longer-term benefits were indicated based on reduced recurrence rates in some patients.

Interesting Biological Explanation of Ketamine Activity

• Forced Swim Test: Measuring the time spent immobile in a forced swim test (an animal model of depression).
• NMDA Receptor Blockade: Ketamine's antidepressant effects are linked to its selective blockade of NMDA receptors.

BDNF Knock-out and Ketamine Action

• BDNF Importance: Ketamine's antidepressant activity requires BDNF protein activation—which involves protein synthesis (translational aspect) rather than activating gene expression.
• Inhibitors: Translation inhibitors prevent ketamine effects, further confirming this aspect.

Circuit Level Explanation of Ketamine's Action

• NMDA and Glutamate Receptors: Inhibitory interneurons are involved, regulated by NMDA receptors and glutamate signaling.
• Ketamine Action: Ketamine preferentially inhibits NMDA glutamate receptors on inhibitory interneurons.

Ketamine's Potential

• FDA Approval: The US has fast-tracked ketamine nasal sprays for FDA approval.
• Revised Treatment: This may need to be revisited based on the most recent research outcome.
• Delayed Treatment: Ketamine treatment is being delayed in the UK.

Slow Increase in Anti-Depression Treatment Armoury

• Monoamine Inhibitors (MAOIs): Inhibit enzymes that break down monoamine neurotransmitters (e.g., MAO-A). Prolonged-time impact based on plasticity changes.
• Tricyclic Antidepressants (TCAs) and Selective Serotonin Reuptake Inhibitors (SSRIs): Inhibit the re-uptake of monoamines, enhancing synaptic levels. Time-dependent plasticity impacts are noted.
• Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs): Enhance noradrenaline and serotonin release and receptor activity; this group often has a strong impact in short-term response.
• Ketamine: Inhibits glutamate neurotransmitter activity, and impacts acute-phase synaptic plasticity but this is not necessarily dependent on long term plasticity mechanisms.
• Psilocybin: Enhances 5-HT receptor signaling, resulting in acute and sustained synaptic plasticity.

Antidepressant Paradox

• Rapid Effect on Monoamine Levels: Drug administration quickly affects the levels of monoamines in the CNS.
• Delayed Clinical Effects: It takes 2 to 6 weeks to see a clinical improvement in patients taking the drugs, signifying a longer-term impact on brain function.
• Predictive Change in Brain Structure: The latency suggests that the treatment produces slower, long-term changes in brain structure and function.

Explore the clinical and neurobiological aspects of affective disorders in this journal club focused on depression and anxiety. Discuss the major features, the monoamine hypothesis, and the role of various antidepressant drugs including novel treatments like ketamine. This quiz will enhance your understanding of current issues in psychiatry and pharmacology.