FHS Behavioral Health Week 2

Psychosis is a combination of clinical symptoms describing a mental state that has lost contact with reality

  • Delusions

  • Hallucinations

  • Disordered thinking


Psychosis is a charcteristic of psych disorders under schizophrenia spectrum and other psychotic disorders


Hallucinations: perceiving things that are not real, such as hearing voices or seeing objects that are not there

Delusions: holding firm to false beliefs that are not based on reality, even when presented with evidence

Disorganized Thinking and Speech: difficulty organizing thoughts and expressing them coherently

Inappropriate Behavior: engaging in actions that are unusual or bizarre

Emotional Disturbances: experiencing intense emotions like fear, anxiety, or depression


Schizophrenia Prevelance

  • 1% of general population

  • Child of two parents with schizophrenia = 40%

  • Monozygotic twin of a schizophrenic parent = 50%

  • Very strong genetic component and environmental components


Schizophrenia Onset

  • Males = 18-25

  • Females = 25-35

    • Women may have a second peak in middle age


Schizophrenia Gender

  • equal in men and women, better outcome for women

  • Birth Season: higher rates in winter and early spring births

  • Stress on mother may lead to higher rates of schizophrenia

    • General systemic inflammation: influenza

  • Geography: higher in urban areas, and certain areas


Schizophrenia Comorbidity

  • higher death rates from accidents and sudden death

  • insuline resistance, hypertension, dyslipidemia, obesity


Risk of Suicide

  • 10-15% commit suicide

  • 50% attempt

    • Risk Factors: male, young, post-psychotic depression, realistic assessment of deterioration due to illness


Substance Use

  • Cigarettes

    • 75-90% of pts smoke

    • Increases metabolism of antipsychotics

    • Nicotine appears to improve some cognitive impairments



DSM-5 Criteria

Schizophrenia

  • at least six months of disturbance with active-phase symptoms (delusions, hallucinations)

  • functional impairment

Schizoaffective

  • combination of schizophrenia-like psych symptoms with major mood episodes

  • psychosis occurring for at least two weeks without the depression or mania



Factors Triggering Psychosis

  • Dysregulation of NT

  • Neuroinflammation

  • Glia

  • HPA Axis

  • Gut microbiome

  • Oxidative stress

  • Mitochondrial dysfunction


Dysregulated Mesolimbic Pathway

  • most prevelent theory is a chemical imbalance in brain, marked by dysregulation of mesolimbic pathway as a result of dopaminergic hyperactivity


Dopamine in Mesolimbic Pathway

  • centers around excessive dopamine activity in the subcortical mesolimbic pathway, linking to the “positive” symptoms

  • elevated striatal dopamine synthesis and release have been correlated to psychosis severity

  • reduced dopamine activity in profrontal cortex associated with “negative” symptoms

  • dopamine dysregulaiton results from upstream NT abnormalities


  • release of dopamine from mesolimbic pathway to nucleus accumbens regulates incentive salience and facilitates reinforcement and reward-related motor function learning

    • Incentive Salience- turns a neutral cue into an intense, magneic desire to seek out reward

  • subjective perception of pleasure

  • dysregulation may lead to addiction


  • goes from ventral tegmental area to nucleus accumbens


Glutamate and Schizophrenia

  • Schizophrenia may involve hypofunction of NMDA receptors, particularly on GABAergic inhibitory interneurons in cortical and limbic circuits

  • Reduced NMDAR activity on inhibitory neurons leds to cortical disinhibition, excessuve glutamate release, and downstream regulation of dopamine and other systems, linking glutamate dysfunction to both psychotic and cogntive/negative symptom domains


  • NMDAR hypofunction leads to impaired glutamate signaling, disrupts the glutamate-glutamine cycle and involves astrocyte-mediated regulation of glutamate

  • Ketamine and phencyclidine cna induce symptoms mimicking schizophrenia


Schizophrenia involves dopaminergic hyperactivity primarily causing positive symptoms and glutamatergic hypofunction contributing to negative symptoms, cognitive deficits, and dopamine dysregulation


reduced NMDA receptor availability/functioning on GABAergic interneurons →

disinhibition of glutamatergic projections onto midbrain dopamine neurons →

increased glutamate release →

increased activation of dopaminergic neurons


Neuroinflammation and Schizophrenia

Neuroinflammation = chronic, low grade immune activation in the brain


Neuroinflammation is characterized by:

  • microglial activation

    • altered morphology, increased inflammatory signaling, elevated binding consistent with reactivity

  • cytokine dysregulation

    • elevated pro-inflammatory cytokines found in blood, CSF, and prefrontal cortex leading to severe symptoms and poor treatment response

    • IL-6

  • oxidative stress and BBB changes

    • inflammatory pathways will increase oxidative stress and can effect the BBB integrity, causing peripheral immune signals to influence brain circuits


How Neuroinflammation contributes to patho:

  • activated microglia release cytokines, reactive oxygen species, and complement factors that:

    • disrupt synaptic pruning and plasticity

      • reduced gray matter and deficits

    • impair NMDA receptor function and GABAergic interneuron health

    • alter dopaminergic signaling

      • reduces dopamine availability and disrupts signaling in brain after a peak in dopaminergic activity

        • leading to lower motivation, fatigue, and feelings of pleasure loss


Glia and Schizophrenia

  • Astrocytes

    • glutamate homeostasis and synaptic support

    • regulate excitatory signaling by clearing synaptic glutamate via transporters

      • in schizophrenia, there are decreased astrocytic glutamate transporters

    • Leads to elevated extracellular glutamate, disrupting the excitation-inhibition balance, contributing to both positive and cognitive symptoms

  • Oligodendrocytes and Myelin

    • connectivity and timing

    • oligodendrocytes myelinate axons to ensure fast and synchronized signal propagation and support axonal metabolism

      • in schizophrenia, there is less oligodendrocyte density, downregulated myelin/oligodendrocyte genes, and white-matter abnormalities meaning there is impaired conduction in the prefrontal circuits

  • Microglia

    • immune surveillance and synaptic pruning

    • coordinate neuroinflammatory response and causes pruning

      • in schizophrenia, activated microglial states, elevated cytokines, and complement pathway alterations may cause excessive or mistimed pruning and oxidative stress, linking immune dysregulation to gray matter loss and cognitive deficits


Hypothalamic-Pituitary-Adrenal Axis and Schizophrenia

  • body’s central stress-response system and its dysregulation may contribute to schizophrenia by linking chronic stress with dopamine, glutamate, immune, and cognitive abnormalities


  • corticotropin-releasing hormone or factor is produced by hypothalamus

  • it reaches the corticotrophs in the anterior pituitary by the hypothalamic-hypophysial-portal system

  • CRH stimulates the synthesis of ACTH

  • ACTH stimulates the synthesis of adrenal steroid hormones

  • cortisol released into the systemic circuit exerts negative feedback inhibition of CRF and ACTH release from hypothalamus and pituitary