Week 3: Mood Disorders: Major Depressive Disorder

Clinical Caveats and Support Services

• Discussions regarding Major Depressive Disorder (MDD) include sensitive topics such as suicide and self-harming behaviors.

• Access to clinical help and crisis support is available through several Australian services:

  • Lifeline: $13\,11\,14$ ($24$-hour free crisis support).

  • Beyondblue: www.beyondblue.org.au

  • Black Dog Institute: https://www.blackdoginstitute.org.au/resources-support/

Overview of Affective Disorders

• Affective disorders are a group of conditions primarily associated with ongoing, severe disruptions to an individual's emotional state.

• Emotional spectrum ranges from positive (happiness) to neutral to negative (sadness). While "depressed" is commonly used to describe a negative mood, its clinical meaning is distinct and specific to a set of diagnostic criteria.

• The Positive and Negative Affect Schedule (PANAS) identifies items associated with these states:

  • Negative items: Distressed, upset, guilty, scared, hostile, irritable, ashamed, nervous, jittery, afraid.

  • Positive items: Interested, excited, strong, enthusiastic, proud, alert, inspired, determined, attentive, active.

• Types of Depressive Disorders:

  • Disruptive Mood Dysregulation Disorder.

  • Major Depressive Disorder (MDD), Single and Recurrent Episodes.

  • Persistent Depressive Disorder (Dysthymia).

  • Premenstrual Dysphoric Disorder.

  • Substance/Medication-Induced Depressive Disorder.

  • Depressive Disorder Due to Another Medical Condition.

  • Other Specified/Unspecified Depressive Disorders.

• Types of Bipolar and Related Disorders:

  • Bipolar I Disorder.

  • Bipolar II Disorder.

  • Cyclothymic Disorder.

  • Substance/Medication-Induced Bipolar and Related Disorder.

  • Bipolar and Related Disorder Due to Another Medical Condition.

  • Other Specified/Unspecified Bipolar and Related Disorders.

Defining Major Depressive Disorder (MDD)

• MDD is an affective disorder characterized by persistent low mood, anhedonia, and a cluster of cognitive and somatic symptoms that significantly interfere with social or occupational functioning.

• Major Depressive Episode (MDE): A discrete time period of at least $2$ weeks where depressive symptoms are experienced.

• MDE is the acute cluster of symptoms, while MDD is the clinical classification based on the history of these episodes.

• Classifications of MDD:

  • Single Episode: The individual experiences one MDE and subsequently recovers.

  • Recurrent: The individual experiences multiple distinct MDEs separated by a minimum break of $2$ months in symptoms.

Prevalence and Epidemiology

• Global Context (WHO, $2017$/$2025$):

  • Estimated total affected: $332$ million people, approximately $4\%$ of the global population.

  • Sex Disparity (Lifetime): $6.9\%$ for females compared to $4.6\%$ for males.

  • Trend: Prevalence rates increased by $18.4\%$ between $2005$ and $2015$. Since $2020$, rates have increased by a further $11\%-25\%$.

• Australian Context (AIHW, $2025$):

  • $12$-month prevalence: $8\%$.

  • Lifetime Sex Disparity: $19\%$ of females vs. $13\%$ of males (aged $16-85$).

  • Mortality ($2024$): Approximately $9$ suicide-related deaths occur per day in Australia.

  • Note: Prevalence is likely higher due to significant underreporting.

Prognosis and the Kindling Effect

• MDD is recurrent and progressive with a variable course.

• Key Predictors: Symptom severity and duration. Longer durations and high severity correlate with poorer outcomes and treatment responsivity.

• Median Duration: $24$ weeks.

• The Kindling Effect (Post, $1992$): Repeated exposure to stressors and subsequent neurochemical changes make future episodes more likely to occur without a clear external cause.

• Probabilities of recurrence:

  • After $1$ episode: $60\%$ chance of a second.

  • After $2$ episodes: $80\%$ chance of a third.

  • After $3$ episodes: $90\%$ chance of a fourth.

Impact of Major Depressive Disorder

• Psychosocial Impacts:

  • Reduced functional capacity in social and occupational settings.

  • Social withdrawal and difficulties forming or maintaining relationships.

  • Loss of workplace productivity; MDD costs government resources and lost productivity approximately $70$ billion per year.

• Comorbidity and Health Impacts:

  • Increased risk of anxiety disorders.

  • Increased risk of physical conditions including obesity and heart disease.

  • Increased disability, morbidity, and all-cause mortality.

  • Reduced quality of life (QOL) leads to overall poorer long-term outcomes.

DSM-5-TR Diagnostic Criteria for MDD

• Criterion A: At least five symptoms present during the same $2$-week period, representing a change from previous functioning. At least one symptom must be (1) depressed mood or (2) loss of interest or pleasure (anhedonia).

1. Depressed Mood: Felt most of the day, nearly every day. May be subjective (feeling sad, empty, hopeless) or observed (tearfulness).

   • Involves emotional blunting or a lack of emotional reactivity.

   • Hopelessness is a predictor of greater severity, chronicity, and suicidal ideation.

   • Irritability is a predictor of greater chronicity and functional impairment.

2. Anhedonia: Markedly diminished interest or pleasure in all or almost all activities.

   • Loss of interest in previously enjoyed hobbies, activities, or social connections.

   • Negativity Bias: Reduced motivation for stimulus with positive connotations.

   • Treatment Predictor: Severe anhedonia correlates with poorer treatment response.

   • Possible Adaptive Value: Cognitive redirection from the external environment to internal processing.

3. Appetite and Weight Changes:

   • Hypophagia: Decreased appetite and food intake leading to weight loss.

   • Hyperphagia: Increased appetite and food intake leading to weight gain.

   • Diagnostic Threshold: Unintentional change of $5\%$ or more in body weight within $1$ month.

   • Associated with problematic behaviors like emotional eating or food addiction.

4. Sleep Disturbances:

   • Insomnia: Chronic inability to sleep. Includes initial (falling asleep), middle (waking up repeatedly), and terminal (waking too early) insomnia.

   • Hypersomnia: Excess of $10$ or more hours of sleep daily; sleep is non-restful, leading to sleep inertia upon awakening and daytime sleepiness.

   • Exacerbates other symptoms such as memory impairment, concentration loss, and irritability.

5. Psychomotor Disturbances: Must be observable by others.

   • Agitation (Restlessness): Inability to sit still, constant pacing, fidgeting, racing thoughts, and increased talkativeness.

   • Retardation (Slowing): Poor eye contact, fixed gaze, slowed speech (flat volume/prosody), and slowed walking speed.

   • Clinical Note: Antidepressants may improve psychomotor changes before other symptoms improve.

6. Fatigue: Loss of energy nearly every day.

   • Lethargy linked to mental or physical exertion.

   • Prevalence: Reported by $73\%-97\%$ of affected individuals.

   • Inversely related to functional capacity; higher fatigue results in lower quality of life.

   • Possible Adaptive Value: Encourages rest to regulate stress and cognition.

7. Negative Self-Thoughts:

   • Guilt: Excessive or inappropriate responsibility for minor failings or uncontrollable circumstances.

   • Worthlessness: Low self-esteem, self-loathing, or feeling like a burden ( >80\% of cases).

   • Rumination (Nolen-Hoeksema, $1991$): Obsessive mental replaying of negative events that prevents concentration and allows other symptoms to intensify.

8. Executive Function (EF) Impairments: Diminished ability to think, concentrate, or make decisions.

   • Includes shortfalls in short-term, working, and visuo-spatial memory.

   • Neuropsychological impacts: Lowered cognitive inhibition, reduced problem-solving capacity, and reduced verbal fluency/mental flexibility (shifting mental sets).

9. Suicidal Ideation: Recurrent thoughts of death or suicide attempts.

   • Passive Ideation: Thoughts without specific intent; a risk factor for active ideation. Contemplated by $78\%-89\%$ of individuals.

   • Active Ideation: Thoughts with intent to act. Assessed via the SLAP framework:

     • Specificity of Plans.

     • Lethality of Method.

     • Availability of Resources.

     • Proximity of Help or Rescuers.

• Criterion B: Symptoms cause clinically significant distress or impairment.

• Criterion C: Episode is not due to substances or another medical condition.

• Criterion D: Not better explained by schizophrenia spectrum disorders.

• Criterion E: No history of manic or hypomanic episodes.

Presentation Specifiers and Heterogeneity

• Substantial Heterogeneity: Because symptoms can be dichotomous (e.g., gain vs. loss of weight) and vary in combination, there are $227$ potential symptom presentations that qualify for an MDD diagnosis (Zimmerman et al., $2015$).

• Severity Specifiers:

  • Mild: $5$ of $9$ symptoms; minor functional impairment.

  • Moderate: $6$ or $7$ of $9$ symptoms; noticeable impairment.

  • Severe: $8$ or $9$ of $9$ symptoms; marked impairment.

• Course Specifiers:

  • Peripartum Onset: Starts during pregnancy or within $4$ weeks of delivery.

  • Seasonal Patterns: Occurs during specific times of year, improving with warmer weather.

  • Remission: Partial or full absence of symptoms for a specific period.

• Episode Specifiers:

  • With Anxious Distress: Feeling tense, restless, or concerned about losing control.

  • With Mixed Features: Presence of some manic/hypomanic symptoms without meeting full criteria for a manic episode.

  • With Psychotic Features: Delusions or hallucinations (often mood-incongruent).

  • With Catatonia: Muscle rigidity or lack of movement.

• Depressogenic Subtypes:

  • Melancholic: ($67\%$ of cases; more common in males). Characterized by non-reactive mood, anhedonia, weight loss, insomnia, loss of libido, and diurnal mood variations. Linked to an overactive HPA axis.

  • Atypical: ($15\%-50\%$ of cases; more common in females). Characterized by mood reactivity, weight gain, hypersomnia, leaden paralysis, and extreme sensitivity to interpersonal rejection. Linked to an underactive HPA axis and rising prevalence in obesogenic environments.

DSM-5 Changes and Differential Diagnosis

• DSM-5 Changes:

  • MDD moved from "Mood Disorders" to a dedicated chapter on "Depressive Disorders," separated from Bipolar disorders.

  • Bereavement Exclusion: Removed the rule that MDD could not be diagnosed within $2$ months of loss; clinicians must now differentiate grief from MDD.

  • Unified Diagnosis: Persistent Depressive Disorder now combines chronic MDD and dysthymia.

• Differential Diagnoses:

  • Bipolar Disorders: Must rule out past manic (Bipolar I) or hypomanic (Bipolar II) episodes.

  • Schizophrenia: Negative symptoms mimic MDD, but SZ psychosis must persist for $2$ weeks in the absence of mood symptoms.

  • Substance/Medication Induced: Mood changes must be Rule out based on toxicology and history.

• Common Comorbidities:

  • Anxiety Disorders: (GAD, Panic Disorder, Social Anxiety) occur in $50\%-60\%$ of lifetime MDD cases.

  • Substance Use Disorders: Higher rates than the general population, often as a coping mechanism.

  • Cardiometabolic Disease: Obesity, Type $2$ Diabetes, and chronic pain, linked by low-grade inflammation and metabolic dysregulation (e.g., leptin).

Aetiological Models of MDD

• Cognitive Models:

  • Beck's Cognitive Model ($1967$): MDD is a product of negative cognitive schemas (self, world, future). Repeated activation leads to an attentional bias specifically toward negative stimuli.

  • Learned Helplessness (Seligman \& Maier, $1970$): Belief that adversity cannot be changed. Categories include Universal (external attributions) and Personal (internal attributions; others could fix it, but I cannot).

  • Rumination (Nolen-Hoeksema, $1991$): Continuous mental replaying reduces motivation, impairs problem-solving, and increases MDD severity.

• Biological Models:

  • Monoamine Hypothesis ($1965$): Deficits in Serotonin (mood, appetite), Norepinephrine (energy), and Dopamine (reward, anhedonia).

  • HPA Axis: Chronic stress leads to hormonal imbalances including Cortisol (fatigue, weight loss), Cytokines (anxiety), Leptin (overeating), and Dopamine (stress response).

  • Brain Structures:

    • Prefrontal Cortex (PFC): Glucocorticoid exposure leads to deficits in memory and emotional regulation.

    • Anterior Cingulate Cortex (ACC): Hypoactivation results in blunted affect and reduced coping.

    • Hippocampus: Smaller volumes are linked to earlier onset and memory impairment.

    • Amygdala: Hyperactivation leads to a bias toward emotional stimuli; activity remains high even after recovery.

  • Genetics: Heritability is estimated at $35\%-45\%$. Concordance in twins is $37\%$. First-degree relatives have a $2-3\times$ higher risk. Potential candidate genes include the serotonin transporter ($5HTT/SLC6A4$).

• Behavioural Models:

  • Interpersonal Theory (Coyne, $1976$): Excessive reassurance seeking leads to social rejection, which perpetuates symptoms.

  • Loss of Positive Reinforcement (Lewinsohn, $1974$): Based on operant conditioning; MDD symptoms arise when positive reinforcers (e.g., income from a job) are removed.

Assessment and Treatment

• Management Team: GPs/Paediatricians (referrals), Psychologists (therapy), and Psychiatrists (medication).

• Psychometric Tools:

  • Clinician-rated: MINI, HAM-D, MADRS (Adults); CBCL, CDRS (Children).

  • Self-Report: BDI-II, DASS, CES-D, PHQ-9, GDRS.

• Pharmacological Treatment (Antidepressants):

  • $1$st Generation: MAOIs (block monoamine oxidase enzymes) and TCAs (block NE and 5HT reuptake).

  • $2$nd Generation: SSRIs (e.g., Lexapro, Prozac, Zoloft) and SNRIs (e.g., Cymbalta, Effexor).

  • Clinical Note: Effects usually take $2-8$ weeks. Side effects include nausea, weight changes, and initial worsening of symptoms.

• Psychological Treatment:

  • Cognitive Behavioural Therapy (CBT) is considered first-line therapy.

  • Components: Goal setting, psychoeducation, cognitive restructuring (reframing), and behavioural activation.

Sociocultural and Social Determinants

• Cultural Variations: Western cultures focus on psychological symptoms (sadness), whereas non-Western cultures may somaticize distress (aches, fatigue). Collectivist cultures may reframe isolation differently than individualistic ones.

• Stigma: Public stigma (viewing MDD as weakness) and self-stigma (shame) delay help-seeking.

• Social Determinants:

  • Low SES/Financial Stress: Resource insecurity increases chronic stress.

  • Unemployment/Education: Lack of autonomy and reduced resources correlate with higher MDD rates.

  • Media: Social media comparisons and constant exposure to negative content lower self-esteem.

• Gender and Marginalization:

  • Women are diagnosed $2\times$ more than men, linked to domestic labor and violence.

  • Masculinity Norms: Men may express distress as irritability or anger due to expectations of stoicism.

  • Marginalization: Discrimination based on identity creates chronic stress environments.