Exam 4, Lec 4: Schizophrenia Anxiety Depression

Symptoms of Schizophrenia

• Positive Symptoms

  • Delusions

  • Hallucinations

  • Disorganized speech

  • Paranoia

  • Grossly disorganized behavior

• Negative Symptoms

  • Decreased motivation

  • Diminished emotional recognition and expression (flat affect)

  • Social withdrawal

  • Poverty of speech

• Cognitive Deficits

  • Impairments in executive function

  • Attention

  • Working memory

  • Episodic memory

  • Language comprehension

Etiology of Schizophrenia: A "Two-Hit" Hypothesis

• Genetic Heredity

  • Accounts for 80-85% of the risk

  • ~50-100 susceptibility genes identified

    • Neuregulin 1 (NRG1)

    • Disrupted-in-schizophrenia 1 (DISC1)

    • Dystrobrevin binding protein 1 (DTNBP1)

• Environmental Risk Factors (approximately 11%)

  • Gestational and birth complications:

    • Oxygen deprivation

    • Drug use

    • Viral infections during the second trimester

    • Severe malnutrition

    • Birth during late winter-early spring months

  • Stressful childhood events:

    • Exposure to toxins

    • Family climate

    • Socioeconomic status

  • Cannabis use during adolescence

    • Functional polymorphism in COMT gene increases risk of developing psychosis (Caspi et al., 2005; Biol Psychiatry)

Neural Causes/Correlates of Schizophrenia

• Abnormalities in Brain Structure

  • Abnormalities in the prefrontal cortex and auditory regions (Broca’s, Wernicke’s areas)

  • Thinned cortex in temporal regions

  • Enlarged ventricles

  • Cerebral atrophy in the temporal lobe, hippocampus, parahippocampal gyrus, and amygdala

  • Abnormal dendrites/disorganization in prefrontal cortex, hippocampus, and entorhinal cortex

  • Lower blood flow in the prefrontal cortex affecting executive function

Dopamine Hypothesis

• Effects of Dopamine

  1. Elevating dopamine in normal individuals can produce schizophrenia-like positive symptoms

  2. Increasing dopamine levels in individuals with schizophrenia can worsen symptoms

  3. Blocking dopamine activity in schizophrenics can reduce symptoms (antipsychotics)

Revised Dopamine Hypothesis

• Positive Symptoms

  • Excess subcortical dopamine (hyperstimulation of D2 receptors in the mesolimbic pathway)

• Negative Symptoms and Cognitive Impairments

  • Deficit in prefrontal dopamine (hypostimulation of D1 receptors in the mesocortical pathway)

  • Associated with defects in a subset of GABAergic interneurons

Treatment of Schizophrenia

• Dopamine Antagonists

  • Chlorpromazine and derivatives, including haloperidol, reduce positive symptoms

  • Gradually effective over time (weeks)

  • Side effects can affect drug compliance:

    • Parkinsonian-like symptoms (tremors, akinesia, muscle rigidity)

    • Tardive dyskinesia (affecting 15-20%) leading to involuntary, purposeless movements

    • Mostly irreversible; thought to be due to postsynaptic DA receptor supersensitization

• Second Generation Neuroleptics

  • Atypical antipsychotics (Clozapine, risperidone, olanzapine)

  • Fewer motor side effects and more effective in reducing negative symptoms

• Third Generation Neuroleptics - Abilify (Aripiprazole)

  • Acts as a partial agonist at D2 receptor

  • Balances dopamine levels by lowering dopamine in areas of excess and stimulating receptors to raise dopamine levels in areas of deficiency

Anxiety versus Fear

• Normal Fear Response

  • Cognitive appraisal: Recognizing and remembering real threats

  • Physiologic arousal: Signals danger, enhances alertness, prepares body for action

  • Behaviors: Fight/Flight/Freezing

Anxiety Disorders

• Emotional Symptoms

  • Irrational and excessive fear or worry

  • Panic

  • Feelings of dread

  • Difficulty concentrating

  • Irritability

  • Restlessness, tension, or jumpiness

• Physical Symptoms (during panic attacks)

  • Pounding heart

  • Sweating

  • Shortness of breath, choking sensations

  • Muscle tension, headaches

  • Fatigue

  • Insomnia

Panic Attack

• Symptoms

  • Intense fear or discomfort with four or more of the following:

    • Palpitations

    • Sweating

    • Trembling

    • Chest pain

    • Dizziness

    • Fear of losing control or dying

    • Numbness

    • Chills or hot flashes

  • Sudden onset and rapid peak (usually within 10 minutes)

  • May be mistaken for a catastrophic medical event

Brain Circuits in Fear

• Key Brain Areas

  • Increased activity in Locus Ceruleus (norepinephrine)

  • Decreased activity in Dorsal Raphe Nucleus (serotonin)

  • Increased amygdala activity (processes sensory information and assigns emotional valence)

  • Hyperactive hypothalamus (autonomic response)

Treating Anxiety: Anxiolytics

• Types of Anxiolytics

  • Benzodiazepines:

    • Sedative-hypnotics (CNS depressants)

    • Examples:

      • Diazepam (Valium): for GAD, PTSD, panic disorder

      • Alprazolam (Xanax): for panic disorder and GAD

    • Quickly relieve psychological and physical symptoms of anxiety, and assist with insomnia

    • Tolerance can develop; risk of dependence and withdrawal

Benzodiazepines and GABA Receptors

• Mechanism of Action

  • Enhance activity of GABA receptors

  • Indirect GABA agonists that increase GABA binding and effect

  • No effect in absence of GABA, making them safer than barbiturates

Depression: The Monoamine Theory

• Theory Overview

  • Clinical depression linked with blunted brain monoamine systems (serotonin and norepinephrine)

  • Evidence includes:

    • Reserpine depletion of monoamines leads to depression in some individuals

    • Antidepressants generally increase monoamine levels

    • Low levels of serotonin in the ventricular fluid of suicide victims

    • Decreased cortex activity in depression, esp. prefrontal cortex

Reserpine

• Historical Context

  • Derived from the Indian snakeroot plant

  • Used for hypertension but caused significant depression in users

  • Works by preventing monoamine transmitters from loading into synaptic vesicles, leading to depletion

Problems with the Monoamine Theory

• Limitations

  • Antidepressants take weeks to show effects despite immediate monoamine increases

  • Lowering monoamines doesn’t consistently lead to depression

  • Elevating monoamines doesn’t reliably improve symptoms

Changes in the Brain Associated with Depression

• Structural Changes

  • Decreased brain volumes in the hippocampus, amygdala, and cortex

  • Impaired HPA function linked to stress

  • Neurotrophic support and neurogenesis issues leading to cell survival concerns

Neuronal Connectivity in Depression

• Overview of Factors Involved

  • BDNF (Brain-Derived Neurotrophic Factor)

  • Glutamate

  • Monoamines

  • CREB (cAMP response element-binding protein)

  • Glucocorticoids

  • Connectivity changes between normal, depressed, and treated states

Brain Activity in Depression

• PET Scans Findings

  • Show overall decreases in brain activity in depressed patients

  • Comparison between unipolar depression and normal states indicates significant variance in activity levels

Causes of Depression

• Genetic Factors

  • Concordance rate of 69% in identical twins vs. 15% in fraternal twins

  • Presence of short alleles of serotonin transporter (5-HTT) increases risk

• Environmental Factors

  • Stress can exacerbate existing conditions but may not directly cause depression

• Gene and Environment Interaction

  • Individual responses to environmental insults can be moderated by genetic history

Gene and Environment Interaction

• Diagram of Interplay

  • Illustrates how genetic predisposition can interact with environmental factors to influence mental health outcomes

Serotonin Gene, Experience, & Depression

• Study Findings

  • Age 26 correlations to abuse levels show a gradient increase in depression risk associated with serotonin gene variations

  • Short alleles linked to greater risk under stressful conditions.