Biochemical Basis of Depression

Biochemical Basis of Depression: Proposed Mechanisms

• Monoamine Deficiency involves decreased serotonin (5-HT), norepinephrine (NE), and dopamine (DA).
• Excessive Upregulation of Cortisol Release indicates HPA Axis dysfunction, like in Cushing Disease/Syndrome; cortisol is neurotoxic in the CNS.
• Hyperinflammation within the CNS, increased expression of pro-inflammatory cytokines, and microglial cell activation leads to neuronal destruction.
• Brain-Derived Neurotrophic Factor (BDNF) deficiency occurs secondary to chronic stress or PTSD.
• Structural Damage to Brain includes Hippocampal and Prefrontal Cortex damage.

Brain Centers Involved with Depression

• Prefrontal Cortex handles rational decision making and goal-motivated behavior.
• Amygdala controls fear and aggression.
• Hippocampus manages memory (learning, cognition) and emotional attachment to memories.
• Ventral Tegmental Area (VTA) and Nucleus Accumbens form reward/pleasure centers.

Serotonergic Receptors

• 5-HT1A post-synaptic receptor is stimulatory and promotes emotional stability, rational decision making, and establishes emotional memory.
• 5-HT1A pre-synaptic receptor (autoreceptor) and 5-HT2A receptor decrease serotonergic activity, worsening depression effects.

Causes of Serotonin Deficiency

• Tryptophan deficiency, a precursor to serotonin, can result from increased inflammation in the brain.
• Decreased serotonin release from the brainstem can be caused by decreased melatonin secretion from the pineal gland.
  • This is a mechanism for seasonal depression.
• Increased activity of 5-HT receptors which DOWNREGULATE serotonergic activity
  • Includes increased presynaptic 5-HT1A and 5-HT2A receptor activity.
• Chronic Inflammation leads to increased microglial cell activity and pro-inflammatory cytokine expression causing neurotoxicity in the brain's emotional centers.
  • Inflammation promotes biochemical shunting of tryptophan into inflammatory biochemical cascades, decreasing available tryptophan for serotonin production.

Norepinephrine (NE)

• NE is produced in the locus coeruleus in the brainstem.
• Causes of NE deficiency include destruction/dysfunction of the brainstem, decreased expression of adrenergic receptors (primarily α1), and increased NET expression.

Norepinephrine (NE) Excess

• Causes of NE excess include hyperinflammation and sleep deprivation.
• Increased NE primarily affects the amygdala, increasing fear and aggression, and the hippocampus, upregulating fight or flight response to traumatic memories.

Dopamine (DA)

• DA deficiency leads to decreased goal-motivated behavior, decreased response to rewarding stimuli, anhedonia, and decreased attachment of abstract/philosophical meaning to emotional events.
• D1 receptors are located in the prefrontal cortex and amygdala.
• D2 receptors are located in the hippocampus and amygdala.

Brain-Derived Neurotrophic Factor (BDNF)

• Normal functions include neurogenesis, neuroplasticity, decreased inflammation, and decreased oxidative stress.
• Deficiency leads to hippocampal and prefrontal cortex atrophy, amygdala hyperreactivity, and decreased neuroplasticity.
  • BDNF typically responds autonomously to antidepressant pharmacotherapy and positive response to therapy.

SIGECAPS Criteria for Depression

• Sleeplessness
• Loss of interest, anhedonia, loss of sexual urges/impotence
• Guilt, feeling worthless
• Decreased energy, fatigue
• Decreased concentration, motivation to learn/adapt
• Appetite changes (usually decreased, can be increased)
• Psychomotor agitations
• Suicidal Ideation

Definitions of Depression

• Major Depressive Disorder: at least 5 SIGECAPS manifestations for 2 weeks, not due to medical causes, with no mania.
• Atypical Depression: depressive phenotypes not meeting major depressive disorder criteria.
• Postpartum Depression: at least 5 SIGECAPS manifestations after delivery for 2 weeks, up to 1 year after delivery.
• Schizoaffective disorder: Depressive phenotypes (not necessarily 5 SIGECAPS) + schizophrenia.
• Seasonal Depression: depressive symptoms at a particular time of year, like winter, improving after the season completes.
  • Decreased sunlight affects melatonin secretion.

Pharmacologic Interventions for Depression

• SSRI's (Sertraline, Fluoxetine, Citalopram, Escitalopram): First line, inhibit 5-HT1A presynaptic and 5-HT2A receptors to increase serotonin.
• SNRI-s (Venlafaxine, Duloxetine): Increase serotonin and NE.
• DNRI (Bupropion): Increases DA and NE.
  • Commonly indicated for smoking cessation.
  • BLACK BOX WARNING: lowers seizure threshold, increasing seizure risk.
• Tricyclic Antidepressants (Amitriptyline): Reserved for treatment-resistant depression.
  • Function as SNRI’s.
  • Cardiotoxicity is a significant side effect.
• MAOI’s (Selegiline, Phenelzine): Patients must AVOID tyramine-containing foods to prevent "tyramine pressor response" which leads to SEVERE HYPERTENSION, dramatically increased risk of stroke!
• Special Antidepressants:
  • Mirtazepine: SNRI enhancing DA release.
    • Agent of choice for patients who desire/require weight gain
  • Trazodone: Serotonin receptor antagonist + NE receptor antagonist + H1 receptor antagonist.
    • Excellent choice for patients with insomnia
    • SIDE EFFECT TO KNOW: Priapism; advise male patients with erections > 4 hours to go to the ER

Serotonin Syndrome

• Hyper-stimulation of serotonergic receptors leads to: autonomic instability, neuromuscular hyperreactivity, acutely altered mental status.
  • Symptoms occur WITHIN HOURS!
• MANAGEMENT:
  • ABC’s
  • IV Benzodiazepines (Lorazepam, Midazolam)
  • IV Fluids + cooling blanket, DO NOT USE ACETAMINOPHEN (TYLENOL)

Schizophrenia

• Genetic Abnormality:
  • GRIN2A deletion predisposes to schizophrenia.
    • Absence decreases glutamate effect, triggers DA increase, and promotes positive symptoms.
• Environmental Factors:
  • History of childhood trauma/abuse, especially sexual abuse, or abuse as an adolescent.
  • History of Cannabis abuse, especially in teenage years
  • History of imprisonment

Schizophrenia Symptoms

• Positive symptoms: Hallucinations, delusions, paranoia, abnormal motor behavior, disorganized thinking/speech.
  • Caused by dopamine hyperactivity.
• Negative symptoms: Apathy/reduced emotional affect, lack of motivation, anhedonia, social withdrawal.
  • Caused by decrease in serotonergic, NE, and DA function.
• Cognitive symptoms: Impaired rational thinking, memory issues, attention deficit, distortions in perspectives.
  • Schizophrenia is a DIAGNOSIS OF EXCLUSION.

Pharmacologic Management of Schizophrenia

• First Generation Antipsychotics (Haloperidol, Fluphenazine, Chlorpromazine):
  • DO NOT USE AS FIRST LINE AGENTS except in extremely rare cases due to side effect profiles (Parkinson-like symptoms, hyperprolactinemia, Cardiotoxicity).
  • Excellent options for non-compliant patients needing IM formulations, but high dosages increase adverse effects risk.
• Second Generation Antipsychotics (Risperidone, Olanzapine, Quetiapine, Aripiprazole, Clozapine):
  • FIRST LINE once the diagnosis of schizophrenia is consolidated
  • Better side effect profile, but increased risk of metabolic syndromes.
  • Clozapine is useful in treatment-resistant, aggressive/violent/suicidal/homicidal patients; monitor for AGRANULOCYTOSIS.

Understanding the biochemical basis of depression involves several key mechanisms. These include monoamine deficiencies, excessive cortisol release, and hyperinflammation within the CNS. Furthermore, Brain-Derived Neurotrophic Factor (BDNF) deficiency and structural damage to the brain also play significant roles.