Depression Pathophysiology

What is Major Depressive Disorder?

When a person experiences 1+ major depressive episodes, without mania or hypomania

Which population is prevalence of mood/anxiety disorders highest in?

Young women (15-24y)

How has the prevalence of mood and anxiety disorders changed in the last decade?

It has increased in all different types of disorders. 

Is there a change in prevalence throughout the year of self-reported anxiety/depression? 

Yes, it often fluctuates with seasonal changes and stressors; with lower prevalence in the summer and higher rates in fall/winter.

Is there difference in prevalence of higher levels of anxiety/depression in provinces across Canada? 

Yes, Ontario residents report higher levels than other provinces. (not most, but more with “worse” symptoms). 

Which patient populations are likely to experience high level of depression?

• caregivers who are concomitantly working

• 18-34 y/o 

• 2SLGBTQIA+ 

• sign of alcohol/cannabis dependency 

• racialized people

• physical impairment 

• income < 30K/y

What is the prevalence of adolescent depression?

Ages 12-17

• females 2x > males

  • 20% vs 8%

How has AI impacted young Canadians as a tool for mental health?

• people are using it 

  • typically < 34 

  • 1/6 people 

What are the non-modifiable risk factors for depression? 

• female sex (in youth and adults; no difference in older adults) 

• family history of mood disorders 

• history of adverse childhood events/maltreatment (esp abuse) 

• death of a spouse

How to genetics play a role as a risk factor for depression?

• if first-degree relative with mood disorders 1.5-3x more likely to develop depression

• estimated 37% heritable

• however also influenced by nurture 

What are the potentially modifiable risk factors for depression? 

• chronic and nonpsychiatric medical conditions

  • chronic pain, CVD, diabetes, cancer, sleep disorders, obesity 

  • bidirectional relationship 

• psychiatric comorbidities 

• alcohol and other substance use disorder (cannabis and alcohol in adolescence)

• insomnia, night shift work

• periods of hormonal changes

  • perinatal and perimenopausal increase risk

• recent stressful life events

• job strain/income inequality

• bereavement (if prolonged/severe)

• peer victimizing/bullying

• gender dysphoria

  • transgender and nongender high risk

• sedentary lifestyle/screen time

What are the different hypotheses for the pathophysiology of depression?

• monoamine hypothesis

• dysregulation hypothesis

• dopamine hypothesis

• inflammation hypothesis

• glutamate and GABA hypothesis 

What is the monoamine hypothesis of depression pathophysiology?

FIX It suggests that depression is associated with a deficiency in the monoamine neurotransmitters, particularly serotonin, norepinephrine, and dopamine, leading to mood disturbances.

What is the dysregulation hypothesis of depression pathophysiology?

FIX It posits that depression results from an imbalance in neurobiological systems, affecting neurotransmitter levels and receptor sensitivity, particularly involving serotonin and norepinephrine.

What is the dopamine hypothesis of depression pathophysiology?

FIX It proposes that diminished dopamine transmission is a critical factor contributing to the symptoms of depression, particularly in relation to motivation and reward.

What is the inflammation hypothesis of depression pathophysiology?

FIX It suggests that inflammatory processes in the brain can lead to changes in neurotransmitter metabolism and neuroplasticity, contributing to the onset and persistence of depressive symptoms.

What is the glutamate and GABA hypothesis of depression pathophysiology?

FIX It posits that imbalances in glutamate and gamma-aminobutyric acid (GABA) neurotransmission may play a significant role in the development of depression, influencing mood regulation and emotional responses.

What investigations need to be done before diagnosing patient with depression? 

• physical exam

• mental status exam

• bloodwork

  • CBC, TSH, Lytes

• rule out medical conditions

  • stroke, PD, traumatic brain injury, hypothyroidism

• medication history

  • to rule out medication-induced 

  • any substance withdrawal 

If a patient is on a medication that can induce depression, does that mean that they do not have depression? 

No, the presence of medication-induced depression does not rule out a primary depressive disorder; it is essential to evaluate the patient's overall mental health. (consider the dose, and what the risk of the med is) 

If a medication that may induce depression is seen on a medication list for a depressed patient, does that mean it has to be stopped?

Not necessarily; the medication may still be necessary, but a careful evaluation of the patient's condition and potential alternatives is required. Need to weight the benefits the medication is providing and the amount the medication might be contributing to the depression. 

What are some medications associated with depressive symptoms?

• isotretinoin (Accutane) → recommend specific psychiatric monitoring 

• antiseizure drugs → warning/precaution suicidal thoughts/behaviour, not all agents (controversial)

• CV meds (ARBs, BBs, CCBs, clonidine, methyldopa) → BBs most evidence supports physical symptoms of fatigue and energy loss, may be disease related

• CNS agents (xx-benazine) → deplete synaptic monoamines via decreased vesicular transport, black block warnings

• Hormones (gonadotropin-releasing, oral contraceptives) → alteration progesterone/estrogen, and maybe MAO activity

• Steroids (prednisone) → maybe due to inflammation and HPA axis changes

• interferons → labeled warning

• varenicline → large post-market research does not support

What are the different classes of clinical symptoms that present in a major depressive episode?

• emotional

• physical 

• psychomotor

• cognitive 

What are the emotional symptoms that present in a major depressive episode?

*most common stereotypical symptoms 

• reduced experience of pleasure

• loss of interest and enjoyment in usual activities, hobbies or work

• hopelessness regarding getting better

• anxiousness (90% outpatients experience)

• voices, internalized negative comments or suggesting suicide

  • if auditory hallucinations to harm themselves, should be hospitalized 

• may feel guilt or delusion deserve their diagnosis, or diagnosis was done to them as a punishment

What are the physical symptoms that present in a major depressive episode?

*may be the reason they go to see MD (esp older adults)

• chronic fatigue effecting ability of daily tasks 

• tiredness that does not improve with rest 

• changes in sleep patterns (60-90% patients experience)

  • difficult to sleep and/or wake up, daytime drowsiness 

  • hypersomnia less commons

• appetite changes 

  • concern if significant weight loss (> 2lbs/week) 

  • may overeat, but find no pleasure in it 

• GI/GU issues

• CV complaints (palpitations) 

• loss of libido 

What are the psychomotor symptoms that present in a major depressive episode?

*often occurs with cognitive symptoms

• slow physical movements, speech, and thought process

• restlessness, outbursts, agitation (psychomotor agitation) 

What are the cognitive symptoms that present in a major depressive episode?

*often occurs with psychomotor symptoms

• aka neurovegitative

• challenges concentrating or slowed thinking

• poor memory of recent events 

• confusion or difficult decision making  

What criteria need to be met to be diagnoses with an MDE? 

• 5+ clinical symptoms that persist most of day 2+ weeks that are new or worsened from baseline:

  • depressed mood and/or lost of interest/pleasure in almost all activities (anhedonia)

  • weight change or ± appetite (> 5%/month)

  • insomnia or hypersomnia

  • psychomotor agitation or slowness

  • tiredness, fatigue, low energy, decreased efficiency

  • worthlessness or excessive/delusional guilt

  • impaired concentration or decision-making

  • suicidal ideation/attempt 

• not explained by illness or substance 

• no history of manic or hypomanic episode (or family history) - rule out bipolar 

What are the different ways to describe a MDE?

• single or recurrent 

• severity → mild, moderate, severe

• episode specifiers: 

  • anxious distress (not enough to diagnose anxiety disorder)

  • mixed features (some mania, but not enough to diagnose bipolar)

  • melancholy 

  • atypical features (cyclic emotions) 

  • mood congruent or incongruent psychosis 

  • catatonia  

What is measurement-based care in MDD management?

• 3 main components: 

  • use validated scales on assessments (track outcomes, side effects, functioning and QoL)

  • review the scores with the patient 

  • use the score + clinical assessment for collaborative decision making 

• associated with higher patient engagement, intervention accuracy and shorter treatment duration

  • easily identify non-responders that may need additional care or alternative treatment modalities 

What are the most common validated scales for depression?

• clinician-rated

  • HAM-D, HAM-7

  • MADRS

• patient-rated

  • PHQ-9

What is the impact of MDD on suicide risk?

• risk of suicide attempts 5x higher in patients with MDD

• ½ of suicide deaths are people with MDD

What are potentially modifiable risk factors of suicide in MDD?

• symptoms and life events

  • suicidal ideation with developed plan and/or intent to act

  • hopelessness

  • anxiety

  • impulsivity

  • psychotic symptoms 

  • stressful life events (financial stress, victimization) 

• comorbid conditions

  • PTSD 

  • SUD (esp alcohol)

  • personality disorders (esp cluster B - antisocial, borderline, histrionic, and narcissistic)

  • sleep disorder 

  • chronic pain (migraine, arthritis) 

When and how should suicide risk be considered in MDD management?

• suicide risk assessment should be routine part of psych interviews

  • assess any reasoning behind though, identify personal strengths and protective factors, and consider future change

  • validated tools exist, but have low predictive value

• if using pharmacological therapy, first month starting or stopping an antidepressant is a high risk period for suicide

  • monitor more closely in this time and have a safety plan in place (removing lethal means, strengthen community support)

What is TRD?

Treatment-Resistant Depression, a form of major depressive disorder that does not respond to typical antidepressant treatments.

• usually means lack of response to 2+ antidepressants at the right dose and duration 

• controversial because:

  • overlooks psychological and neurostimulation - assuming switching best first step and avoids add-on strategies 

  • “failure” inconsistently defined and does not account for partial responses or lingering symptoms 

  • “resistant” can be discouraging and seem like any future treatment is futile

• used when referring to specific medication options or studies that use these terms

What is DTD?

Difficult to treat depression, a persistent depression that has failed numerous (> 2) treatments, and is further on the treatment trajectory

• provides a more supportive terminology for patients when discussing poor responses

• describes a journey when treatments not effective

  • manage symptoms versus full remission

  • aim for best improvement in patient preferred areas like QoL