Schizophrenia Spectrum Overview

Schizophrenia Spectrum

• Schizophrenia is characterized by distorted perceptions and normal functions, often associated with increased dopamine activity in the mesolimbic pathway.

• Positive Symptoms: These involve excessive or distorted normal functions, and include hallucinations (perceiving stimuli without external input), delusions (false, strong beliefs despite evidence), disorganized speech, and disorganized behavior (unpredictable or inappropriate actions)

• Pathophysiology of Positive Symptoms: Positive symptoms are linked to hyperactivity of dopamine in the mesolimbic pathway (nucleus accumbens and hippocampus). Dopamine agonists can induce psychotic symptoms, whereas dopamine D2 antagonists can reduce positive symptoms.

• Negative Symptoms: These involve the absence or reduction of normal behaviors and emotional responses, often leading to social withdrawal and emotional blunting. Examples include flattened affect (reduced emotional expression), anhedonia (inability to experience pleasure), alogia (limited speech output), and avolition (lack of motivation).

• Pathophysiology of Negative Symptoms: Negative symptoms are thought to be caused by hypoactivity of dopamine in the mesocortical pathway, which projects to the prefrontal cortex. They are also associated with decreased glutamatergic activity and reduced GABA levels in the dorsolateral prefrontal cortex.

• Cognitive Symptoms: These impact a person's thought processes, severely impairing daily functioning. Examples include working memory deficits, poor executive functioning (issues with planning, problem-solving and task switching), reduced attention and concentration.

• Pathophysiology of Cognitive Symptoms: These issues are linked to dopamine hypoactivity in the mesocortical pathway and NMDA receptor dysfunction. Dysregulation of GABAergic signaling in the prefrontal cortex may also contribute to poor inhibitory control.

Summary of Pathophysiology Overview

• Mesolimbic pathway hyperactivity: causes positive symptoms
• Mesocortical pathway hypoactivity: causes negative and cognitive symptoms
• GABA and glutamate dysregulation: contributes further to cognitive decline and affective flattening.

Neuroanatomical and Neurotransmitter Alterations

• Enlarged Ventricles: Reduced brain tissue volume is often linked to cognitive impairment and negative symptoms.
• Loss of Gray Matter: Schizophrenia is associated with cortical thinning and loss of gray matter in the frontal and temporal lobes.
• Abnormalities in Prefrontal Cortex (DLPFC): Reduced activity leads to working memory, attention, and decision-making deficits. This can contribute to negative symptoms and cognitive decline.
• Dopamine Hypothesis: Dysregulated dopamine activity in different brain regions contributes to schizophrenia's symptoms.
  • Mesolimbic pathway (positive symptoms): Increased dopamine release is linked to positive symptoms (hallucinations, delusions, paranoia). D2 receptor antagonists (antipsychotic drugs) reduce these.
  • Mesocortical pathway (negative and cognitive symptoms): Low dopamine activity contributes to these.
• Glutamate Hypothesis: Underactivation of NMDA receptors, particularly in the prefrontal cortex and hippocampus, affects synaptic plasticity, learning, and memory. Drugs like PCP and ketamine can induce schizophrenia-like symptoms due to NMDA receptor blockage.
• GABA Dysfunction: Reduced GABA activity (particularly in the dorsolateral prefrontal cortex) leads to hyperexcitability. This affects cognitive performance and may contribute to both negative and cognitive symptoms.
• Serotonin Dysfunction: Elevated serotonin activity may contribute to positive symptoms (hallucinations and delusions.) Atypical antipsychotics (target both dopamine and serotonin) can be effective.
• Interconnected Neural Circuits: The limbic system and thalamus display dysregulation in schizophrenia
• These combined factors contribute to the complex and multifaceted pathology of schizophrenia.