Schizophrenia and Dopamine Levels
No, schizophrenia is not characterized by overall low dopamine levels—rather, it involves a regional imbalance with excessive dopamine activity in subcortical mesolimbic pathways (causing positive symptoms) and deficient dopamine activity in cortical regions, particularly the prefrontal cortex (causing negative and cognitive symptoms). 1, 2, 3
The Dopamine Imbalance Model
The pathophysiology of schizophrenia reflects a complex regional dysregulation rather than a simple excess or deficit:
Subcortical Dopamine Excess
- Mesolimbic dopamine hyperactivity is associated with positive symptoms including hallucinations, delusions, and thought disorder 1, 2
- Neuroimaging studies using SPECT and PET demonstrate substantially increased dopamine transmission in subcortical regions of schizophrenic patients compared to healthy controls, particularly after amphetamine challenge 3
- Acute dopamine depletion studies reveal increased baseline occupancy of D2 receptors by dopamine in schizophrenia, consistent with hyperstimulation of these receptors 3
Cortical Dopamine Deficit
- Prefrontal cortex dopamine deficiency is hypothesized to underlie negative symptoms (blunted affect, anhedonia, asociality, inability to complete complex tasks) and cognitive impairment 1, 2
- D1 receptors are up-regulated in the dorsolateral prefrontal cortex of schizophrenic patients, likely representing a compensatory mechanism for dopamine deficit 3
- This cortical D1 receptor up-regulation correlates with poor performance on working memory tasks (n-back test) 3
The Cortical-Subcortical Interaction
- Prefrontal dopamine neurons normally inhibit subcortical dopamine activity 2
- The leading hypothesis suggests that abnormally low prefrontal dopamine activity causes deficit symptoms while simultaneously leading to disinhibition and excessive mesolimbic dopamine activity that produces positive symptoms 2
- This explains the concurrent presence of both positive and negative symptom clusters in the same patient 2
Neurotransmitter Systems Beyond Dopamine
While dopamine dysregulation is central, schizophrenia involves multiple neurotransmitter disturbances:
- Glutamate and dopamine systems are both implicated in schizophrenia pathophysiology, with these distinct etiological processes likely converging to cause neurobiological disturbances 4
- Schizophrenic patients may have increased serotonin levels and decreased norepinephrine levels compared to healthy subjects 1
Treatment Implications
Understanding this regional imbalance is critical for treatment:
- Conventional antipsychotics nonselectively block dopamine D2 receptors throughout the CNS, which reduces positive symptoms but has little effect on negative symptoms 1
- Newer atypical antipsychotics have more anatomically selective dopaminergic activity and additional actions on serotonin and norepinephrine systems, contributing to greater therapeutic efficacy on both positive and negative symptoms 1
- The American Academy of Child and Adolescent Psychiatry recommends atypical antipsychotics as preferred first-line treatment for equivalent efficacy on positive symptoms with better tolerability 5
Critical Caveats
- Schizophrenia does not reflect primary abnormalities of dopamine transmission but rather abnormalities in systems that intimately interact with dopamine pathways, including fronto-striato-pallido-thalamic loops and limbic structures 6
- The dopamine hypothesis remains limited in theoretical scope and does not apply uniformly to all schizophrenic patients 7
- Direct evidence supporting the dopamine hypothesis is either uncompelling or has not been widely replicated; indirect pharmacological evidence provides the major support 7