BMS150 Wk 6 lec 1

Overview of Psychiatry

• Psychiatry is the branch of medicine that focuses on the prevention, assessment, and treatment of mental, emotional, and behavioral disorders.
• Disorders include substance abuse/addictions, mood, anxiety, eating disorders, personality disorders, and psychotic disorders.
• Treatments can include medications, psychotherapy, electroconvulsive therapy, and other forms of medicine.

Common Psychiatric Presentations

• Delusion: a belief that is clearly false and indicates an abnormality in the content of thought.
  • False belief cannot be explained by the person's cultural or religious background or intelligence level.
  • Belief is held despite being presented with evidence against it ("fixed" – firmly maintained).
  • Can be due to mental disorder, neurological or medical disorder.
  • Examples: schizophrenic, substance abuse, bipolar disorder, major depressive disorder (MDD), delirium, and dementia.
• Hallucination: a sensory perception in the absence of a corresponding external or somatic stimulus and described according to the sensory domain in which it occurs.
  • Not under voluntary control.
  • Vivid, clear, full force, and impact of normal perceptions.
  • Examples: visual, auditory, tactile, olfactory, gustatory, nociceptive, thermoceptive, proprioceptive, equilibrioceptive.

Major Depressive Disorder (MDD)

• Epidemiology:
• Major clinical features:
• Diagnostic Criteria (DSM-5):
  • Additional diagnostic requirements:
    • Sx must cause significant distress or impair social, occupational, or other important areas of function.
    • Sx are not due to direct physiological effects of a substance (e.g., meds, drug abuse) or medical condition (e.g., hypothyroidism).
    • Px has never experienced a manic or hypomanic episode.
    • This condition is not better explained by schizophrenia spectrum or other psychotic disorders.

Neuropathology and Neurochemistry of MDD

• Multifactorial disease with various causes and triggers:
  • Psychosocial causes.
  • Genetics.
  • Nutritional deficiencies.
  • Pollution/environment.
  • Gut-brain axis.
• Leading biomedical theories:
  • Monoamine hypothesis.
  • Stress-induced depression hypothesis.
  • Neurotrophic/neuroplasticity hypothesis.
  • Cytokine hypothesis/neuroinflammation hypothesis.
  • Circadian hypothesis of depression.
  • GABA-glutamate-mediated depression hypothesis.

Monoamine Hypothesis

• Altered levels of monoamine neurotransmitters, specifically serotonin and noradrenaline, and/or dopamine cause depression.
• Based on antidepressant therapies that increase the presence/function of one or more neurotransmitters, resulting in reduced depression.
• Critique: abruptly decreasing serotonin and/or dopamine doesn't cause depression in a healthy person.

Stress-Induced Depression Hypothesis

• Chronic stress leads to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis.
  • Prolonged, moderate stress is the problem, versus minor daily stresses or one strong stressor.
  • Examples: maternal stress, maternal smoking, early grave loss, child abuse.
  • Early trauma may have more significant impact than in adult life (impact how HPA is developed in utero).
  • Chronic HPA activation leading to: excess cortisol secretion and pro-inflammatory agents that damage glia and neurons, interfere with neurogenesis, and reduce glutamate and GABA.

Neurotrophic and Neuroplasticity Hypothesis

• Brain-derived neurotrophic factor (BDNF) promotes neurogenesis, regulates differentiation and growth of neurons.
• Neurogenesis may offer resilience against stress by enhancing the negative feedback loop with HPA.
• Observations:
  • Decreased BDNF gene expression, decreased BDNF levels and receptors in MDD patients.
  • Increased cortisol can inhibit BDNF.
  • Same triggers that elevated cortisol appear to block neurogenesis.
• Antidepressants:
  • Have been demonstrated to stimulate neurogenesis in adult hippocampus (animal studies) – takes 4 weeks.
  • Correlates with the 3-4 week expectation of achieving improvement in mood.

Cytokine and Neuroinflammation Hypothesis

• Observation:
  • MDD patients have increased levels of pro-inflammatory markers: TNFalpha, IL-1, IL-6, C-reactive protein (CRP) vs. healthy patients, as well as increased level of macrophage/monocyte activation.
  • Frequent correlation between MDD and inflammatory conditions such as asthma, diabetes, arthritis, obesity, CAD.
  • Animal studies: injecting pro-inflammatory cytokines induces depressive symptoms.
  • Some antidepressants have anti-inflammatory properties.
  • Earlier case reports observed improvement in mood in patients with treatment-resistant MDD treated with anti-inflammatory medications, particularly in the context of other inflammatory conditions (like IBD).

Circadian Hypothesis

• Healthy state:
  • Light inhibits pineal gland from producing melatonin (by activating neurons with suprachiasmatic nucleus (SCN) of the hypothalamus).
  • SCN regulates production of melatonin throughout the body.
  • Melatonin production increases at night during conditions of dark.
• Circadian hypothesis:
  • Stressful events lead to changes in diurnal molecular rhythms in cells that in vulnerable patients trigger MDD.
  • Bidirectional link with sleep disturbance and depression.
    • Insomnia is a predisposing factor.
    • Sleep deprivation therapy – reduces MDD symptoms (may reset the circadian clock).
    • Genes controlling circadian rhythms in anterior cingulate cortex are dysregulated in depression.
    • Phase advance in cortisol rhythm and reduced amount of melatonin production seen in some patients with MDD.
    • Altered circadian rhythms can also affect reward systems, particularly social interaction.
    • Same 5-HT receptors have been implicated in both sleep rhythms and depression; serotonin is involved in phosphorylation of CLOCK protein, which regulates suprachiasmatic circadian rhythms.

Excitatory Neurotransmitters Hypothesis

• Glutamate may cause excitotoxicity resulting in neuronal atrophy and reduced synaptic connectivity.
  • Stress-induced changes may be accelerated in the presence of elevated Glu.
  • Reduced GABA in CSF of MDD patients – may be due to change in serotonin, which modulates GABA, which in turn modulates glutamate.
• Reduced GABA and glutamate within glial cells and neurons of the prefrontal cortex (PFC).
  • Astrocytes recycle glutamate and transport to presynaptic neurons.
• Elevated metabolism of glucose within same areas of PFC, and reduction of the gray matter in this region.
• Ketamine – modulates glutamate transmission:
  • Approved for tx of treatment-resistant MDD.

Antidepressant Mechanisms of Action

• Possible mechanisms of antidepressant action:
  • Reuptake inhibitors:
    • Immediate: increase levels of NT's (ex., serotonin).
    • Delayed: down-regulation of NT receptors.
      • Could explain time needed to see antidepressant effects.
      • The 5HT1a receptors are autoreceptors – they inhibit release of NT from presynaptic terminals.
        • If they're down-regulated → increased NT release.
      • Sustained antidepressant therapy is also associated with increased production of BDNF, which is likely linked to efficacy.

Antidepressant Suicide Risk

• Take home: increased suicide risk in children, adolescents, and young adults up to 24 years of age when taking antidepressants.

SSRI's: Serotonin Syndrome

• Serotonin syndrome can occur in response to increased serotonin levels.
  • Often caused by a combo of two drugs (e.g., SSRIs and MAOIs).
  • Can also be caused by a “high-normal” dose in a sensitive individual.
• Triad of symptoms:
  • Altered mental status:
    • Anxiety, agitation, disorientation.
  • Autonomic hyperactivity:
    • Diaphoresis, mydriasis, tachycardia, hyperthermia, hypertension, dramatic swings in pulse & bp, vomiting, and diarrhea.
      • Patient is often hot and sweating with a fast heart rate and high blood pressure that goes up and down.
  • Neuromuscular abnormalities:
    • Tremor, clonus, muscle rigidity, hyperreflexia, bilateral Babinski sign.
      • Hyperreflexia and clonus are particularly common and are more often pronounced in the lower extremities.

Treatment of Serotonin Syndrome

• Remove the causative agent.
• Interfere with serotonin action:
  • Cyproheptadine can be given – what do you think its therapeutic mechanism might be?
• Symptomatic treatment:
  • Treat the agitation with benzodiazepines (BDZ).

This quiz covers an overview of psychiatry, definitions of common psychiatric presentations, and in-depth information on Major Depressive Disorder and Bipolar Disorders, including epidemiology, clinical features, diagnostic criteria, and neurochemistry/neuropathology. Ideal for BMS 150 students.