Exam 2 - Biological Basis of Psychiatric Disorders

Learning Objectives

• Identify factors that impact psychiatric disorders

• Identify major NT pathways and brain regions

• Explain theories of the etiology of major psychiatric disorders: schizophrenia, depression

• Contrast the support for these theories with the weaknesses of each theory

What biological factors contribute to psychiatric disorders?

• Genetic: heritable changes to DNA sequences or copy numbers

• Environmental factors: prenatal changes, infections, exposure to toxins, injuries, substance abuse

• Epigenetics: heritable changes in phenotype by environment without changes to DNA sequences (DNA/chromatin packing, DNA chemical structure may be altered)

What are biologic correlates for psychiatric disorders?

• Genetic differences (GWAS, association studies)

• Brain structures changes (aka anatomical differences; i.e. reduced gray matter)

• Changes in neurophysiological function (EEG)

• Imaging (MRI, PET)

• Neurotransmitter & receptor function

• Bodily fluid constituents

  • Blood & urine

What neurotransmitters are in important/involved with psychiatric disorders?

• Monoamine NTs

  • Catecholamines: Norepi and dopamine

  • Serotonin (5-HT) → 5-hydroxytryptamine

• Glutamate (excitatory NT)

  • N-methyl-D-Aspartate (NMDA) receptors

  • Important receptor implicated in psychiatric disorders

What are the dopamine pathways?

1) Nigrostriatal

2) Mesolimbic

3) Mesocortical

4) Tuberoinfundibular

What function does the nigrostriatal dopamine pathway have?

Movement (i.e. Parkinson’s disease)

What function does the mesolimbic dopamine pathway have?

Emotion (schizophrenia)

Reward (addiction potential)

What function does the mesocortical dopamine pathway have?

Emotion, reasoning (schizophrenia)

What function does the tuberoinfundibular dopamine pathway have?

Release of pituitary hormones (hyperprolactinemia)

What is the dopamine hypothesis of schizophrenia?

Hypothesis: Schizophrenia results from the functional overactivity in the mesolimbic dopamine pathway (emotional and reward) and functional hypoactivity in the mesocortical dopamine pathway (reasoning)

What pieces of evidence support this hypothesis?

• Dopamine stimulant drugs (like cocaine, amphetamines) induce psychotic symptoms in normal patients

• Effective antipsychotic meds are dopamine antagonists

What are weaknesses of the dopamine hypothesis of schizophrenia?

• Antipsychotics block dopamine receptors acutely, but therapeutic effect is not seen until 2-6 weeks into treatment

• It is difficult to demonstrate functional dopamine abnormalities in untreated schizophrenic patients

What is the glutamate hypothesis of schizophrenia?

Schizophrenia results from a functional hypoactivity in brain glutamate mediated by the NMDA receptors resulting in a functional hyperactivity in dopamine

• AMPA receptors may also play a role

What supports the glutamate hypothesis?

• Phencyclidine (PCP), which is an NDMA antagonist, induces psychotic reactions resembling schizophrenia

• Some evidence of NMDA receptor abnormalities in schizophrenic brains

What kind of drug is ketamine?

NMDA open channel inhibitor

What are the immediate antidepressant effects of low doses of ketamine?

• Ketamine causes downstream release of glutamine

• Subanesthetic doses of ketamine exerts immediate antidepressant effect in treatment-resistant unipolar and bipolar patients

• Can immediately reduce suicidal thoughts

What is the monoamine hypothesis of depression?

Depression results from a relative decrease in the neurotransmitter transmission (norepinphrine, 5-HT (serotonin), and dopamine)

• mania results from a relative increase in norepinephrine or 5-HT transmission).

What pieces of evidence support the dopamine hypothesis of depression?

• Reserpine depletes NE, 5-HT, and dopamine and causes clinical depression

• Depression can be induced by acute depletion of tryptophan (precursor of 5-HT)

• 5-HT metabolite levels in CSF are lower in some patients with MDD

• Monoamine oxidase inhibitors (MAOI) inhibit degradation of NE and 5-HT and serve as antidepressants

• NE and 5-HT reuptake inhibitors (SSRIs) are antidepressants

What is the neurotropic hypothesis of depression?

The nerve growth factors such as brain-derived neurotrophic factor (BDNF) are critical in the regulation of neural plasticity, resilience, and neurogenesis

What pieces of evidence support the neurotrophic hypothesis of depression?

• Loss of neurotrophic support is seen in depression

• Direct infusion of BDNF into certain brain regions has antidepressant-like effects in animal model

• Antidepressants increase BDNF levels after chronic, but not acute, administration

• Antidepressants increase neurogenesis and synaptic connectivity in cortical areas (e.g. hippocampus)

• BDNF activates the tyrosine kinase receptor B (TrkB) in both neurons

What are weaknesses of the neurotropic hypothesis?

• BDNF knockout mice didn’t always show increased depressive or anxious behaviors

• BDNF levels are not increased in all animal models of depression

• Direct infusion of BDNF into the lateral ventricle increased depressive behaviors

What is the neurodevelopmental hypothesis of schizophrenia?

Development of abnormal brain circuits or synaptic disorganization that leads to symptoms seen in teens and early 20s

• Abnormal cell migration during the second trimester of pregnancy

• Respiratory infections during the second trimester of pregnancy