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Understanding Depressive Disorders

Feb 24, 20256 min read

Etiology and Pathogenesis of Depressive Disorders

  • Biochemical: A deficit of specific neurotransmitters in the brain mainly Serotonin, Noradrenaline, and Dopamine
  • Psychosocial: Factors like low self-esteem and dependent personalities
  • Social: Life events and stress
  • Developmental factors: Genetic and hereditary factors
  • Integrative: Involves all previous factors

Areas in Brain Affected by Depression

  • Limbic System
  • Hypothalamus

DSM Qualifiers of Mood States (Coded with Main Diagnosis)

  • Atypical features: Overeating, oversleeping while depressed; preserved reactivity to reward.
  • Catatonic Features: Detachment from the environment while awake; negativism including immobility, mutism, refusal to eat or drink. May be life-threatening.
  • Melancholic Features: Dense anhedonia, lack of response to reward, terminal insomnia (early morning awakening), diurnal variation (mornings worse).
  • Postpartum onset: Depressive episode within 1 month of childbirth by definition. Clinically, this period of markedly increased risk may be ≥ 3 months. Often includes marked anxiety.
  • Psychotic features: Mood congruent in depression: Delusions of poverty, guilt, nihilism, illness, self-disgust; derogatory auditory hallucinations.
    • Mood congruent in mania: Delusions of special powers or unlimited resources, paranoia, auditory hallucinations.

A 21st Century View of Depression

  • Environmental factors: (including external environment: psychosocial stressors, sleep deprivation, internal environment: gonadal/HPA steroids)
  • Behavior: Cognitive/Affective/Sensorymotor
  • Systems: Critical circuitry
  • Cellular:
    • Cell growth/survival/death
    • Cell morphology: dendritic remodeling
  • Molecular:
    • Susceptibility genes
    • Protective genes
    • Transcription factors
    • mRNA

BDNF, CREB, PKC, and other regulatory proteins Key message: From the neurobiological perspective, a new clinical outlook of depression encompasses the understanding of molecular, cellular, chemical, behavioral and environmental factors of depression.

BDNF = brain-derived neurotrophic factor; CREB = cAMP responsive element binding;
HPA = hypothalamic-pituitary-adrenal; mRNA = messenger ribonucleic acid; PKC = protein kinase C;

Schloesser RJ et al. 2008. Neuropsychopharmacol Rev. 2008;33:110-33.

Depression: A Disease of the Mind, Brain, and Body

  • Prefrontal cortex
  • Hypothalamus
  • Amygdala
  • Locus ceruleus
  • Cytokines
  • Cortisol
  • Increased sympathetic outflow
  • ACTH
  • Adipose tissue
  • Bone
  • Adrenal gland

Gold PW, Charney DS. Am J Psychiatry. 2002;159(11):1826.

It is known that depression is an illness that affects the mind and mood of a sufferer, altering that person’s core experience of others and the world around them. There is emerging evidence that depressed patients have a significant loss of cells in the prefrontal cortex. An increase in cortisol and norepinephrine secretion represents a highly adverse biochemical environment, a condition that is likely to contribute to many different adverse outcomes, including increased

Major Depressive Disorder May Have Systemic Consequences

  1. Hypothalamus stimulates pituitary gland to release excessive ACTH, continuously driving the adrenal gland
  2. Adrenal gland releases excessive amounts of catecholamines and cortisol
  3. Increase in catecholamines can lead to myocardial ischemia, diminished heart rate variability, and can contribute to ventricular arrhythmias
  4. Increase in catecholamines causes platelet activation; increase in cytokines and interleukins may also contribute to atherosclerosis and eventual hypertension
  5. Cortisol antagonizes insulin and contributes to dyslipidemia

ACTH=Adrenocorticotropic hormone
Adapted from Musselman DL et al. Arch Gen Psychiatry 1998;55(7):580-92.

Depression and Chronic Disease

  • Chronic illness has been associated with increased prevalence of depression
  • Diseases include:
    • Diabetes
    • Hypertension
    • Cardiovascular diseases
    • Mild cognitive impairment prior to onset of dementia
    • Cancer
    • HIV
    • COPD
    • Rheumatoid arthritis

HIV = human immunodeficiency virus; COPD = chronic obstructive pulmonary disease
Simon GE. West J Med 2001;175:292-3; de Groot et al., Diabetes Spectrum 2010;23:15-8;
Scalco et al. Clinics 2005;60:241-50; Barnes DE et al. Arch Gen Psychiatry 2006;63:273-80; Lin HB et al. Ann Fam Med 2009;7:414-21.

Prevalence Rates of Depression in Chronic Medical Disorder

  • General Population
  • Chronically III
  • Hospitalized
  • Older Inpatients
  • Cancer Outpatients
  • Cancer Inpatients
  • Stroke
  • MI
  • Parkinson’s Disease

… I FEEL SO DEPRESSED!

  • YES, YES, YES - but has there been any family history of asthma, diabetes, high blood pressure?
  • What about heart disease, liver disease, kidney trouble?

Martin Davis 1997

Signs

  • Depressed For

    • No Reason
    • Depressed For
      • A Good Reason

  • JUST DEPRESSED,

    • DON’T WANT TO
    • ANALYZE IT

Structural Changes in Brain in Depression

  • Depression
    • Decrease in neurogenesis
    • Decrease in hippocampal volume
    • Cellular atrophy

Cellular Atrophy in Depression

  • Rat hippocampal neurone before (A) and after (B)
  • 3-week repeated stress

Evidence of Hippocampal Atrophy and Loss in Patients With MDD

  • **Compared to controls, patients with depression had smaller hippocampal volumes (n=16)**1
  • Decreased hippocampal volume may be related to the duration of depression2−4
  1. Brenner JD, et al. Am J Psychiatry. 2000;157(1):115-118.
  2. Sheline YI, et al. J Neurosci. 1999;19(12):5034-5043.
  3. Sheline YI, et al. Proc Natl Acad Sci USA. 1996;93(9):3908-3913.
  4. Sheline YI, et al. Am J Psychiatry. 2003;160(8):1516-1518.

Images courtesy of JD Bremner.

Barriers to Diagnosis and Treatment in the Arab Countries

  • Lack of education about depression
  • Lack of availability of appropriate therapies
  • Competing clinical demands
  • Social issues
  • Lack of patient acceptance of the diagnosis

Depression is one of the most common causes of morbidity in developing countries. It is believed that there are many barriers to diagnosis and treatment in the primary care setting. Through a sample of 50 primary health care providers working in the public health clinics of the Jordanian Ministry of Health (MOH), it was identified that the lack of education about depression, lack of availability of appropriate therapies, competing clinical demands, social issues, and the lack of patient acceptance of the diagnosis were among the most important barriers to the identification, diagnosis, and treatment of patients with depression in this population. REFERENCE: Nasir LS, Al-Qutob R. Barriers to the diagnosis and treatment of depression in Jordan. A nationwide qualitative study. Am Board Fam Pract. 2005 Mar-Apr;18(2):125-31.

Freud

“Melancholia, whose definition fluctuates even in descriptive psychiatry, takes on various clinical forms the grouping together of which into a single unity does not seem to be established with certainty; and some of these forms suggest somatic rather than psychogenic affections.”

Mourning and Melancholia (1917)

Are Depressed Patients More Likely to Be Medically Ill?

  • 1500 Depressed Patients were evaluated for General Medical Conditions
  • Total prevalence was 53%
  • Those with older age, lower income, unemployment, limited education and longer duration of depression were at higher risk
Disease / SystemPrevalence %
Musculoskeletal43%
Respiratory32%
Heart29%
Upper GI26%
Neurological25%
Endocrine24%

Yates et al, Gen Hosp Psych 2004
STAR-D Study

Likelihood of Depression Increases with No. of Physical Symptoms at Presentation

Kroenke K, et al. Arch Fam Med 1994
Out patient data. High utilizers are ususally depressed, anxious or somatization d/o or substance abuser

Medical Screening for Mood Episodes Should Include:

  • Review of systems, physical exam, blood count and chemistries, thyroid function tests, and tests for auto-immune factors. Other studies (EKG, neuroimaging) should be obtained only if indicated by specific symptoms, not just abnormal mood.

Differential Diagnosis of Depression

  • Grief
  • Medical causes
  • Other psychiatric disorders

What is Grief?

  • Grief is the physical, emotional, somatic, cognitive and spiritual response to actual or threatened loss of a person, thing or place to which we are emotionally attached. We grieve because we are biologically willed to attach. (John Bowlby, Father of Attachment Theory)

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